Search

Classical histological methods such as hematoxylin-eosin staining, have been, and in some areas still are, an important benchmark for the evaluation of biological tissues. However, the current method of assessment is primarily a qualitative assessment of the tissue under investigation. The aim of this paper is to contribute to the improvement of classical histological methods, by applying physical techniques that allow objective, quantitative data to be added to qualitative assessments, especially in areas where conflicting results are available. To this end, the effect of hypolipidemic medication on the callus formation process of normal bone and pathological osteoporotic bone was investigated. The study allowed us to associate UV-VIS spectroscopy wave number with specific hematoxylin-eosin staining of different types of bone tissue structures, the evolving structures in the callus formation process. This association allowed the quantitative assessment of the callusing process in ovariectomized (associated with pathological, osteoporotic bone) and non-ovariectomized (associated with normal bone) rats, with three groups - the control group, simvastatin-treated group, and fenofibrate-treated group. The study showed that in the non-ovariectomized groups both treatments delayed callus formation. In the ovariectomized groups, simvastatin delayed and fenofibrate promoted callus formation.

Background: Non-alcoholic fatty liver disease (NAFLD) has been increasing in association with the epidemic of obesity and diabetes. Peroxisomes are single membrane-enclosed organelles that play a role in the metabolism of lipid and reactive oxygen species. The present study examined the role of peroxisomes in high-fat diet (HFD)-induced NAFLD using fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist.Methods: Eight-week-old male C57BL/6J mice were fed either a normal diet or HFD for 12 weeks, and fenofibrate (50 mg/kg/day) was orally administered along with the initiation of HFD.Results: HFD-induced liver injury as measured by increased alanine aminotransferase, inflammation, oxidative stress, and lipid accumulation was effectively prevented by fenofibrate. Fenofibrate significantly increased the expression of peroxisomal genes and proteins involved in peroxisomal biogenesis and function. HFD-induced attenuation of peroxisomal fatty acid oxidation was also significantly restored by fenofibrate, demonstrating the functional significance of peroxisomal fatty acid oxidation. In Ppara deficient mice, fenofibrate failed to maintain peroxisomal biogenesis and function in HFD-induced liver injury.Conclusion: The present data highlight the importance of PPARα-mediated peroxisomal fitness in the protective effect of fenofibrate against NAFLD.

Background: The Japan Pharmaceutical Association has conducted drug event monitoring to detect drug events related to pemafibrate. As there are a few studies on the safety of pemafibrate in clinical settings, a pilot study evaluating the association between drug use and detected events was performed in Japan. Aim: In this study, the association between detected events and the use of pemafibrate, utilizing pharmacy records maintained by community pharmacists, was investigated. We identified the newuser cohort using a test and active comparison drug and collected the baseline information. An active comparison group comprising new users was used to assess the events. Method: A retrospective cohort study using questionnaires regarding baseline and event data was conducted by community pharmacists belonging to the Japan Pharmaceutical Association. The incidence of event and estimated hazard ratio were calculated using the Cox proportional hazards model that was adjusted for confounding factors, such as age and sex. Results: A total of 1294 patients using pemafibrate and 508 patients using fenofibrate were identified as new drug users. The most reported events involving suspected adverse reactions and add-on drugs were increased blood pressure and lipid-lowering effects with pemafibrate use, and nasopharyngitis, pruritus, dizziness, and lipid-lowering effects with fenofibrate use. No significant differences were found in commonly occurring events, except that an add-on anti-hypertensive drug has been used by pemafibrate users compared to fenofibrate users. Conclusion: This study conducted by pharmacists can facilitate the safety assessment of newly marketed drugs, as few drug use investigations with a comparator are carried out by the Japanese authority for pharmaceutical companies. However, further research is required.

NF-κB family of transcription factors are the major contributors to malignant tumor progression, maintenance of cancer stemness, and enhancement of chemoresistance. Fenofibrate, a lipid-lowering drug, has been considered as a candidate for repurposing in the treatment of cancer through various pathways involved in apoptosis, cell cycle, migration, and invasion, including NF-κB. Nevertheless, whether fenofibrate possesses the potential to inhibit cancer stemness remained to be examined.Cytotoxicity of fenofibrate was estimated by MTT assay. The cells expressing stemness marker were detected by flow cytometry using ALDEFLUOR™ Kit. The secondary sphere formation assay was used to assess the self-renewal ability. Transwell system was used to evaluate migration and invasion capacities. NF-κB expression was measured by the immunoblotting system.In the present study, we demonstrated that fenofibrate inhibited cell viability, expression of stemness marker, self-renewal, migration, and invasion capacities in a dose-dependent manner. Of note, fenofibrate targeted cancer stem cells of oral squamous cell carcinoma (OSCC-CSCs) and had minimal effects on normal cells. Moreover, administration of fenofibrate at a lower concentration was sufficient to diminish the expression of NF-κB p50 and p65.This study demonstrated that the inhibitory effects of fenofibrate on OSCC-CSCs properties may be associated with downregulation of NF-κB. These results indicated that administration of fenofibrate may serve as an alternative strategy for OSCC therapy.

In this study, we investigated the effects of ingested water volume on the oral absorption of fenofibrate (FEN) with several formulations to confirm the applicability of rats for oral formulation screening. Oral absorption of suspended crystalline FEN was significantly improved by increasing ingested water volume (from 0.5 to 2 mL). FEN absorption improvement by particle size reduction and the linearity in oral absorption by dose escalation suggested that the rate-limiting step of FEN absorption in rats was the dissolution rate, consistent with that in humans. When FEN, as an amorphous solid dispersion (ASD) formulation, was suspended in water followed by immediate administration, oral FEN absorption was significantly higher than when administered in crystalline form and was not influenced by the differences in ingested water volume. Oral absorption of FEN from encapsulated ASD formulation in 1 or 2 mL of water was comparable with that of the suspension form. However, 0.5 mL of water significantly reduced the oral absorption of the solid ASD FEN formulation. These results indicate that to improve the oral absorption of poorly water-soluble drugs when performing a preclinical study with rats, 1 mL of water is the minimum preferable ingested volume to evaluate in vivo formulation performance.

Financiado para publicación en acceso aberto: Universidade de Vigo/CISUG Introduction Fenofbrate is an agonist of peroxisome proliferator activated receptor alpha (PPAR-α), that possesses antiinfammatory, antioxidant, and anti-thrombotic properties. Fenofbrate is efective against a variety of viral infections and diferent infammatory disorders. Therefore, the aim of critical review was to overview the potential role of fenofbrate in the pathogenesis of SARS-CoV-2 and related complications. Results By destabilizing SARS-CoV-2 spike protein and preventing it from binding angiotensin-converting enzyme 2 (ACE2), a receptor for SARS-CoV-2 entry, fenofbrate can reduce SARS-CoV-2 entry in human cells Fenofbrate also suppresses infammatory signaling pathways, which decreases SARS-CoV-2 infection-related infammatory alterations. In conclusion, fenofbrate anti-infammatory, antioxidant, and antithrombotic capabilities may help to minimize the infammatory and thrombotic consequences associated with SARSCoV-2 infection. Through attenuating the interaction between SARS-CoV-2 and ACE2, fenofbrate can directly reduce the risk of SARS-CoV-2 infection. Conclusions As a result, fenofbrate could be a potential treatment approach for COVID-19 control.

The Peroxisome Proliferator-Activated Receptor-alpha (PPARα) is a member of the ligand-dependent nuclear receptor superfamily known for their crucial role in lipid metabolism. The expression and role of PPARα in trophoblast cells are not very well known. Trophoblast invasion is one of the most critical processes required for successful implantation of the developing embryo into the maternal endometrium. Defects in this process are associated with adverse pregnancy outcomes such as FGR(Fetal Growth Restriction), Preeclampsia, and choriocarcinoma. In this present study, we investigated the role of the ligand-activated transcription factor, Peroxisome proliferator-activated receptor (PPARα) in regulating trophoblast cell invasion using cell lines and explants-based models. Immunohistological localization of PPARα in human placental tissues showed a gestational variation with relatively low expression at term as compared to early trimester. PCR and Western Blot also confirmed this. Further to delineate the effect of PPAR alpha on trophoblast invasion, EVT derived HTR8/SVneo cell lines were stimulated with PPARα agonist, i.e., fenofibrate (FF). Fenofibrate stimulation led to an increased activation and nuclear translocation of PPARα, followed by reduced migration and invasion of these cells in a matrigel invasion assay (Boyden chamber). PPAR alpha stimulation also led to a reduced MMP-2/9 expression following our previous observation. Thus, we may conclude that PPARα to be playing a very important regulatory role in orchestrating the invasive trophoblast programme and hence it seems plausible for it to be associated with PE, which is often characterized by a shallow trophoblast invasion.

Despite treatment with statins, dyslipidaemia patients with elevated cholesterol- and triglyceride-levels remain at high residual risk for major adverse cardiovascular events (MACE). New lipid-lowering drugs must prevent the occurrence of MACE and exhibit cost-effectiveness for their successful adoption to clinical practice.To assess the cost effectiveness of icosapent ethyl, fenofibrate, ezetimibe, evolocumab, and alirocumab in combination with statins compared to statin monotherapy for cardiovascular prevention from the perspective of UK's National Health Service.A Markov model simulated the progression of cardiovascular disease and MACE, including myocardial infarction, stroke, angina pectoris, and coronary revascularisation, in dyslipidaemia patients. The model was populated with cardiovascular outcome trial data for each drug. Cost and utility data were extracted from peer-reviewed literature. The incremental cost-effectiveness ratio (ICER) is reported per quality-adjusted life years (QALY) gained in 2021 Great Britain Pounds (£).For primary cardiovascular prevention, icosapent ethyl increased QALYs by 0.79 and costs by £15,421 compared to statin monotherapy (ICER = £19,485/QALY). Fenofibrate yielded 0.62 additional QALYs at cost-savings of - £6127 (ICER = - £9932/QALY). For secondary prevention, the omega-3 fatty acid icosapent ethyl extended QALYs by 0.98 at costs of £12,981 compared to statin monotherapy (ICER = £13,285/QALY). Fenofibrate added 0.85 QALYs whilst saving - £637 (ICER = - £7472/QALY). Ezetimibe increased QALYs by 0.60 at cost reductions of - £2529 (ICER = - £4231/QALY). PCSK9 inhibitors provided QALYs of 0.53 and 0.86 at costs of £45,279 and £46,375 for evolocumab (ICER = £85,193/QALY) and alirocumab (ICER = £54,211/QALY), respectively. At a willingness-to-pay threshold of £25,000/QALY, there is a probability of 100% for icosapent ethyl (98% in primary prevention) and 0% for PCSK9 inhibitors to be cost effective in secondary prevention.Icosapent ethyl is cost effective for primary and secondary cardiovascular prevention at an annual price of £2064 in the UK. For PCSK9 inhibitors, price discounts or prescription restrictions are necessary to achieve cost effectiveness.

Objectives The aim of this study was to assess the short-term safety and efficacy of fenofibrate in controlling secondary hypertriglyceridemia in cats. Methods This was a prospective cohort study. Seventeen adult cats with hypertriglyceridemia (serum triglycerides [TG] >160 mg/dl) were enrolled. Cats received a median dose of 5 mg/kg (range 3.2–6) fenofibrate (q24h PO) for 1 month. Serum TG, total cholesterol (TC), creatine kinase and liver enzymes (alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase) were evaluated before (t0) and after 1 month (t1) of fenofibrate treatment. Results The causes of secondary hypertriglyceridemia were diabetes mellitus (DM; 29.4%), obesity (29.4%), hyperadrenocorticism (HAC) and DM (11.7%), HAC without DM (5.9%), hypersomatotropism (HST) and DM (5.9%), hypothyroidism (5.9%), long-term treatment with glucocorticoids (5.9%) and chylothorax (5.9%). Serum TG (t0 median 920 mg/dl [range 237–1780]; t1 median 51 mg/dl [range 21–1001]; P = 0.0002) and TC (t0 median 278 mg/dl [range 103–502]; t1 median 156 mg/dl [range 66–244]; P = 0.0001) concentrations showed a significant decrease after 1 month of fenofibrate treatment. Fifteen cats normalized their TG concentration at t1 (88.2%). Of the eight cats that were hypercholesterolemic at t0, six (75%) normalized their TC concentrations at t1. One of 17 cats (5.9 %) presented with diarrhea; the remaining 16 did not show any adverse effects. Conclusions and relevance DM and obesity are the most common endocrine causes of secondary hyperlipidemia, although it can also be found in cats with HAC, HST or hypothyroidism. This study suggests that fenofibrate treatment was associated with reduction and normalization of TG and TC concentrations in cats with moderate and severe hypertriglyceridemia, regardless of the cause of secondary hypertriglyceridemia. Further work should focus on controlled studies with a greater number of cases.

Treatment with acetyl-CoA carboxylase inhibitors (ACCi) in nonalcoholic steatohepatitis (NASH) may increase plasma triglycerides (TGs), with variable changes in apoB concentrations. ACC is rate limiting in de novo lipogenesis and regulates fatty acid oxidation, making it an attractive therapeutic target in NASH. Our objectives were to determine the effects of the ACCi, firsocostat, on production rates of plasma LDL-apoB in NASH and the effects of combined therapy with fenofibrate. Metabolic labeling with heavy water and tandem mass spectrometric analysis of LDL-apoB enrichments was performed in 16 NASH patients treated with firsocostat for 12weeks and in 29 NASH subjects treated with firsocostat and fenofibrate for 12weeks. In NASH on firsocostat, plasma TG increased significantly by 17% from baseline to week 12 (P= 0.0056). Significant increases were also observed in LDL-apoB fractional replacement rate (baseline to week 12: 31 ± 20.2 to 46 ± 22.6%/day, P= 0.03) and absolute synthesis rate (ASR) (30.4-45.2mg/dl/day, P= 0.016) but not plasma apoB concentrations. The effect of firsocostat on LDL-apoB ASR was restricted to patients with cirrhosis (21.0 ± 9.6 at baseline and 44.2 ± 17mg/dl/day at week 12, P= 0.002, N= 8); noncirrhotic patients did not change (39.8 ± 20.8 and 46.3 ± 14.8mg/dl/day, respectively, P= 0.51, N= 8). Combination treatment with fenofibrate and firsocostat prevented increases in plasma TG, LDL-apoB fractional replacement rate, and ASR. In summary, in NASH with cirrhosis, ACCi treatment increases LDL-apoB100 production rate and this effect can be prevented by concurrent fenofibrate therapy.

Background Numerous fixed-dose combinations (FDCs) of cilnidipine (CIL) with chlorthalidone (CLT) and azilsartan medoxomil (AZL) are used for the treatment of hypertension. Numerous reverse-phase high-pressure liquid chromatography (RP-HPLC) and high-performance thin-layer chromatography (HPTLC) methods have been reported in the literature for the estimation of FDCs of CIL. But no HPTLC method has been reported yet for synchronous estimation of multiple FDCs of CIL to save time, organic solvent, and cost of analysis. In the recent scenario of green chemistry, the minimum usage of organic solvent in the development of the chromatographic method is highly desirable for the safety of the environment and analysts. Objective Hence, a robust and green HPTLC method has been developed for the synchronous estimation of multiple FDCs of CIL using the analytical quality by design (AQbD) approach. Methods The chemometric tool was applied for the identification of the critical method variables (CMVs) and critical analytical attributes (CAAs) for the HPTLC method development. The design of experiments (DoE) was applied for the response surface analysis of identified CMVs and CAAs using the Box-Behnken design. The analytical design space and control strategy was framed for the lifecycle management of the HPTLC method. Results The chromatographic separation was performed using silica gel G60 F254 as the stationary phase and toluene–ethyl acetate–methanol (6.5 + 2 + 1.5, v/v) as the mobile phase. The method was validated as per the International Council for Harmonization Q2 (R1) guideline. The developed method was applied for the synchronous estimation of multiple FDCs of CIL, and results were found in compliance with labeled claims. Conclusions The developed HPTLC method can be used as a green, economical, and rapid analytical tool for routine analysis and quality control of multiple FDCs of CIL in the pharmaceutical industry. Highlights Development of a HPTLC method for synchronous estimation of multiple FDCs of CIL using the AQbD approach based on principles of chemometry and DoE. Application of the developed method for synchronous assay of multiple FDCs of CIL to save time, cost, and solvent for analysis.

OBJECTIVE Patients with type 2 diabetes (T2D) have a high risk for developing heart failure (HF), which is associated with poor prognosis. Fenofibrate may reduce HF events through multiple mechanisms. We sought to study the effect of fenofibrate (vs. placebo) in HF outcomes among patients with T2D receiving simvastatin enrolled in the Action to Control Cardiovascular Risk in Diabetes lipid trial (ACCORD Lipid). RESEARCH DESIGN AND METHODS We used Cox regression analysis with background glucose-lowering strategy as the stratification variable. The median follow-up was 4.7 years. RESULTS A total of 5,518 patients were included. Median age was 62 years, and 31% were women. Prior HF history was present in 5% of the patients. The composite outcome of HF hospitalization or cardiovascular death occurred in 190 (6.9%) patients in the fenofibrate group vs. 228 (8.3%) in the placebo group: HR 0.82, 95% CI 0.68–1.00 (P = 0.048). The beneficial effect of fenofibrate to reduce HF hospitalizations or cardiovascular death was present among patients receiving standard glucose-lowering strategy, HR 0.64, 95% CI 0.48–0.85, and not among patients receiving intensive glucose-lowering strategy, HR 1.02, 95% CI 0.79–1.33 (Pinteraction = 0.017). A similar pattern was observed for HF hospitalizations alone. The effect of fenofibrate on blood lipids was not influenced by background glucose-lowering therapy in a clinically important manner. Fenofibrate caused more transient worsening estimated glomerular filtration rate (eGFR) events but slowed long-term eGFR decline. CONCLUSIONS In patients with T2D treated with simvastatin, fenofibrate reduced the composite of HF hospitalizations or cardiovascular mortality, an effect that was seen predominantly in patients with standard background glucose-lowering therapy.

An electrochemical chemosensor for cilostazol (CIL) determination was devised, engineered, and tested. For that, a unique conducting film of the functionalized thiophene-appended carbazole-based polymer, molecularly imprinted with cilostazol (MIP-CIL), was potentiodynamically deposited on a Pt disk electrode by oxidative electropolymerization. Thanks to electro-oxidation potentials lower than that of CIL, the carbazole monomers outperformed pyrrole, thiophene, and phenol monomers, in this electropolymerization. The pre-polymerization complexes quantum-mechanical and molecular dynamics analysis allowed selecting the most appropriate monomer from the three thiophene-appended carbazoles examined. The electrode was then used as a selective CIL chemosensor in the linear dynamic concentration range of 50 to 924 nM with a high apparent imprinting factor, IF = 10.6. The MIP-CIL responded similarly to CIL and CIL's pharmacologically active primary metabolite, 3,4-dehydrocilostazol (dhCIL), thus proving suitable for their determination together. Simulated models of the MIP cavities binding of the CIL, dhCIL, and interferences' molecules allowed predicting chemosensor selectivity. The MIP film sorption of CIL and dhCIL was examined using DPV by peak current data fitting with the Langmuir (L), Freundlich (F), and Langmuir-Freundlich (LF) isotherms. The LF isotherm best described this sorption with the sorption equilibrium constant (

Objective: In the present study, we attempted to identify the effects of fenofibrate on human cervical cancer cells. Methods: The cytotoxicity of fenofibrate in cervical cancer cells was determined by Cell Counting Kit-8. Immunoblotting assay was used to determine the protein expression of caspase-3, poly ADP-ribose polymerase cleavage, B-cell lymphoma 2 family protein expression, microtubule-associated protein 1A/1B-light chain 3 (LC3), as well as cyclins and cyclin-dependent kinases. Immunofluorescence imaging was used to determine the expression of cleaved caspase-3 and LC3. Flow cytometry was used to determine cell cycle and apoptosis. Results: We first showed that fenofibrate treatment reduced cell viability in HeLa cervical cancer cells in a dose-dependent manner at 24 h and 48 h. Importantly, fenofibrate-induced cell death was mediated through cell cycle arrest in the G0–G1 phase and caspase-dependent apoptosis. Moreover, fenofibrate also induced autophagy activation in a dose-dependent manner and pharmacological inhibition of autophagy led to increase of sub-G1 phase and caspase-dependent cell death in HeLa cells. Conclusion: In conclusion, these data demonstrated that fenofibrate initially induced cell cycle arrest, followed by caspase-3-dependent cell death in cervical cancer HeLa cells. However, fenofibrate also induced autophagy activation, which is closely related to the survival of diverse cancer cells, thus reducing the anticancer effects of fenofibrate. Therefore, the combination of an autophagy inhibitor and fenofibrate might have the potential to become a new therapeutic strategy for cervical cancer.

Background & aimsPatients with advanced fibrosis due to nonalcoholic steatohepatitis (NASH) are at high risk of morbidity and mortality. We previously found that a combination of the farnesoid X receptor agonist cilofexor (CILO) and the acetyl-CoA carboxylase inhibitor firsocostat (FIR) improved liver histology and biomarkers in NASH with advanced fibrosis but was associated with hypertriglyceridemia. We evaluated the safety and efficacy of icosapent ethyl (Vascepa) and fenofibrate to mitigate triglyceride elevations in patients with NASH treated with CILO and FIR.MethodsPatients with NASH with elevated triglycerides (≥150 and

Introduction: Surface engineering of nanocrystals for improving the biopharmaceutical features is a multivariate process involving numerous formulation and process variables, thus making it a complicated process to get the desired biopharmaceutical quality profile. Nano-by-design is hereby proposed as an approach to nanonize an orally active, lipid lowering fenofibrate, to improve feasibility in product development. Methodology: Top-down wet ball milling (media milling) in zirconia planetary chamber was methodically explored for improving the solubility and bioavailability of fenofibrate by formulating a nanosuspension using polyvinyl alcohol as a stabilizer. Several influencing variables were screened using a systematic one-factor-at-a-time approach. DSC, SEM, XRD, and FTIR were utilized for physical characterization of the product during the development stage and study the effect of milling time, milling speed, fenofibrate: stabilizer ratio, premilling time and stabilizer concentration. Potential risk factors affecting critical quality biopharmaceutical attributes of fenofibrate nanocrystals like size, zeta potential, in vitro release, crystallinity and intrinsic solubility were optimized to improve pharmacokinetic performance. Result: Formulated nanosized fenofibrate exhibited a crystalize nature as evident from XRD and DSC, 411 nm size, and a rapid but complete dissolution (~99% in 30 min). This resulted into quick onset of action and improved bioavailability as observed from 51.46% shorter Tmax, 82.63% higher Cmax, and 69.34% higher AUC0–24h, respectively.

Background. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of liver damage, affecting ~25% of the global population. NAFLD comprises a spectrum of liver pathologies, from hepatic steatosis to nonalcoholic steatohepatitis (NASH), and may progress to liver fibrosis and cirrhosis. The presence of NAFLD correlates with metabolic disorders such as hyperlipidemia, obesity, blood hypertension, cardiovascular, and insulin resistance. Fenofibrate is an agonist drug for peroxisome proliferator-activated receptor alpha (PPARα), used principally for treatment of hyperlipidemia. However, fenofibrate has recently been investigated in clinical trials for treatment of other metabolic disorders such as diabetes, cardiovascular disease, and NAFLD. The evidence to date indicates that fenofibrate could improve NAFLD. While PPARα is considered to be the main target of fenofibrate, fenofibrate may exert its effect through impact on other genes and pathways thereby alleviating, and possibly reversing, NAFLD. In this study, using bioinformatics tools and gene-drug, gene-diseases databases, we sought to explore possible targets, interactions, and pathways involved in fenofibrate and NAFLD. Methods. We first determined significant protein interactions with fenofibrate in the STITCH database with high confidence (0.7). Next, we investigated the identified proteins on curated targets in two databases, including the DisGeNET and DISEASES databases, to determine their association with NAFLD. We finally constructed a Venn diagram for these two collections (curated genes-NAFLD and fenofibrate-STITCH) to uncover possible primary targets of fenofibrate. Then, Gene Ontology (GO) and KEGG were analyzed to detect the significantly involved targets in molecular function, biological process, cellular component, and biological pathways. A P value < 0.01 was considered the cut-off criterion. We also estimated the specificity of targets with NAFLD by investigating them in disease-gene associations (STRING) and EnrichR (DisGeNET). Finally, we verified our findings in the scientific literature. Results. We constructed two collections, one with 80 protein-drug interactions and the other with 95 genes associated with NAFLD. Using the Venn diagram, we identified 11 significant targets including LEP, SIRT1, ADIPOQ, PPARA, SREBF1, LDLR, GSTP1, VLDLR, SCARB1, MMP1, and APOC3 and then evaluated their biological pathways. Based on Gene Ontology, most of the targets are involved in lipid metabolism, and KEGG enrichment pathways showed the PPAR signaling pathway, AMPK signaling pathway, and NAFLD as the most significant pathways. The interrogation of those targets on authentic disease databases showed they were more specific to both steatosis and steatohepatitis liver injury than to any other diseases in these databases. Finally, we identified three significant genes, APOC3, PPARA, and SREBF1, that showed robust drug interaction with fenofibrate. Conclusion. Fenofibrate may exert its effect directly or indirectly, via modulation of several key targets and pathways, in the treatment of NAFLD.

OBJECTIVE: Patients with type 2 diabetes (T2D) have a high risk for developing heart failure (HF), which is associated with poor prognosis. Fenofibrate may reduce HF events through multiple mechanisms. We sought to study the effect of fenofibrate (vs. placebo) in HF outcomes among patients with T2D receiving simvastatin enrolled in the Action to Control Cardiovascular Risk in Diabetes lipid trial (ACCORD Lipid). RESEARCH DESIGN AND METHODS: We used Cox regression analysis with background glucose-lowering strategy as the stratification variable. The median follow-up was 4.7 years. RESULTS: A total of 5,518 patients were included. Median age was 62 years, and 31% were women. Prior HF history was present in 5% of the patients. The composite outcome of HF hospitalization or cardiovascular death occurred in 190 (6.9%) patients in the fenofibrate group vs. 228 (8.3%) in the placebo group: HR 0.82, 95% CI 0.68–1.00 (P = 0.048). The beneficial effect of fenofibrate to reduce HF hospitalizations or cardiovascular death was present among patients receiving standard glucose-lowering strategy, HR 0.64, 95% CI 0.48–0.85, and not among patients receiving intensive glucose-lowering strategy, HR 1.02, 95% CI 0.79–1.33 (P(interaction) = 0.017). A similar pattern was observed for HF hospitalizations alone. The effect of fenofibrate on blood lipids was not influenced by background glucose-lowering therapy in a clinically important manner. Fenofibrate caused more transient worsening estimated glomerular filtration rate (eGFR) events but slowed long-term eGFR decline. CONCLUSIONS: In patients with T2D treated with simvastatin, fenofibrate reduced the composite of HF hospitalizations or cardiovascular mortality, an effect that was seen predominantly in patients with standard background glucose-lowering therapy.

In the recent years scientific and technological advancements have been made in the research and development of oral drug delivery systems. The aim of this study was to formulate and evaluate of orodispersible tablets by direct compression for fenofibrate by using super fast disintegrating agents like croscarmellose sodium. The use of super disintegrant and excipient for preparation of fast disintegrating is highly effective and commercially feasible. In the present investigation poorly water soluble drug is one of the most important parameters of oral formulations sucessfully developed fenofibrate was using solvent evaporation method drug: PEG 6000 in (1:5 w/w). The formulation F7 was the optimized formula that showed satisfactory results with various physicochemical evaluation parameters like thickness, hardness, weight variation, friability, drug content, % drug release almost 79.98% within 15 min. and it was follow the maximum higuchi release kinetics that regression coefficient values ‘r2’= 0.995.

Introduction: The present study deals with the synthesis of pregnane-oximino-amino-alkyl-ethers and their evaluation for antidiabetic and anti-dyslipidemic activities in validated animal and cell culture models. Methods: The effect on glucose tolerance was measured in sucrose-loaded rats; antidiabetic activity was evaluated in streptozotocin (STZ)-induced diabetic rats and genetically diabetic db/db mice; the anti-dyslipidemic effect was characterized in high-fructose, high-fat diet (HFD)-fed dyslipidemic hamsters. The effect on glucose production and glucose utilization was analyzed in HepG2 liver and L6 skeletal muscle cells, respectively. Results: From the synthesized molecules, pregnane-oximino-amino-alkyl-ether (compound 14b) improved glucose clearance in sucrose-loaded rats and exerted antihyperglycemic activity on STZ-induced diabetic rats. Further evaluation in genetically diabetic db/db mice showed temporal decrease in blood glucose, and improvement in glucose tolerance and lipid parameters, associated with mild improvement in the serum insulin level. Moreover, compound 14b treatment displayed an anti-dyslipidemic effect characterized by significant improvement in altered lipid parameters of the high-fructose, HFD-fed dyslipidemic hamster model. In vitro analysis in the cellular system suggested that compound 14b decreased glucose production in liver cells and stimulated glucose utilization in skeletal muscle cells. These beneficial effects of compound 14b were associated with the activation of the G-protein-coupled bile acid receptor TGR5. Conclusion: Compound 14b exhibits antidiabetic and anti-dyslipidemic activities through activating the TGR5 receptor system and can be developed as a lead for the management of type II diabetes and related metabolic complications.

Background Drug-induced liver injury (DILI) is the leading cause of acute liver failure in the United States. DILI is mainly caused by painkillers and fever reducers, and it is often characterized by the type of hepatic injury (hepatocellular or cholestatic). This report presents a case of fenofibrate-induced severe jaundice in a 65-year-old Korean male with no prior history of liver disease. We offer a strategy for patients who present signs of severe liver injury with jaundice and high elevations in serum transaminases. Case summary A 65-year-old male visited the gastroenterology outpatient clinic of a tertiary hospital due to increased levels of liver enzyme and total bilirubin which were incidentally detected through a preoperative screening test. Abdominal ultrasound and computed tomography showed no biliary obstruction or non-specific findings in the liver. Liver biopsy was performed and the patient was finally diagnosed with acute cholestatic hepatitis. Following the biopsy, steroid therapy was initiated and after 3 wk of treatment, the total bilirubin level was reduced to 7.22 mg/dL. Conclusion In patients with hyperlipidemia, treatment including fenofibric acid induces rare complications such as severe jaundice and acute cholestatic hepatitis, warranting clinical attention.

PURPOSE Residual cardiovascular risk reduction by fenofibrate in patients with high serum triglyceride (TG) levels despite previous statin monotherapy is not well characterized. The purpose of this study was to evaluate the efficacy and safety of a combination of choline fenofibrate and statin in patients with inadequately controlled TG levels despite previous statin monotherapy. METHODS This prospective, multicenter, randomized, double-blind study was conducted in Korea. A total of 133 patients with controlled LDL-C but elevated TG levels, already receiving statin monotherapy, were enrolled in the study, which was conducted from July 2018 to December 2019. Patients were randomly assigned to receive combination therapy with choline fenofibrate and statin or statin monotherapy in a 1:1 ratio. After 8 weeks of treatment, the lipid profiles and safety parameters of the patients in the 2 groups were compared. FINDINGS The study included 127 patients (64 in the combination group and 63 in the control group) older than 19 years. After 8 weeks of therapy, mean serum TG levels significantly decreased from 269.8 to 145.5 mg/dL (P < 0.0001) in the combination therapy group, whereas no significant changes occurred in the statin monotherapy group (from 271.1 to 280.5 mg/dL). Contrarily, the mean serum HDLC levels significantly increased from 45.0 to 50.4 mg/dL (P = 0.0004) in the combination therapy group, whereas there were no significant changes in the monotherapy group (from 44.3 to 44.7 mg/dL). There were no additional serious adverse events in the combination therapy group compared with the statin monotherapy group. IMPLICATIONS The combination therapy using choline fenofibrate and statin was found to be effective in serum TG control and likely tolerable in patients with high TG levels despite statin monotherapy. A larger study, conducted for a longer duration, is needed to evaluate the effectiveness of this combination in reducing cardiovascular risk. ClinicalTrials.gov identifier: NCT03874260.

Aims: A accurate, precise, and stability-indicating Reversed-Phase HPLC technique has been established for the estimation of fenofibrate in tablet formulation. Study Design: Experimental study. Place and Duration of Study: Department of Pharmaceutical Sciences, RTM Nagpur University, Nagpur-440033, Maharashtra, India between June 2019 and March 2020. Methodology: The chromatographic separation was attained on RP Princeton column (C18) (250 mm x 4.6 mm, 5 µ) with mobile solvent system as a mixture of water (pH 3.0 along o-phosphoric acid) and acetonitrile in the proportion (40:60) v/v, flow rate 1.0 ml per minute, at 240 nm. The retention time of fenofibrate was 3.905 minutes. Results: The method demonstrated linearity in the concentration range of 87-232 µg/ml with a coefficient of correlation (r2) of 0.9994. The % RSD was ˂2% and percentage recovery was found to be 99.13-100.74%. The assay of marketed tablet formulations was found to be 99.98%. Conclusion: The developed and validated technique as per ICH rules for specificity, accuracy, precision, linearity, and system suitability. Reverse Phase-HPLC technique was utilized to the market formulation.

Maternally inherited diabetes and deafness is a rare genetic disease mainly caused by a point mutation in mitochondrial deoxyribonucleic acid. Lipoprotein lipase gene mutations are associated with familial dyslipidemias, which are difficult to manage. We reported for the first time a case that had both maternally inherited diabetes and severe hyperlipidemia caused by lipoprotein lipase gene mutation (C.347(exon3)G>C) that was resistant to fenofibrate and atorvastatin. We were able to manage the patient’s hyperlipidemia with bezafibrate, and her diabetes was well controlled with insulin. In conclusion, genetic testing is helpful in identifying rare and interesting cases when clinicians suspect inheritable diseases. Additionally, when one fibrate drug is ineffective in treating hyperlipidemia, it might be worthwhile trying another fibrate.

Cancer and its associated conditions have significant impacts on public health at many levels worldwide, and cancer is the leading cause of death among adults. Peroxisome proliferator-activated receptor α (PPARα)-specific agonists, fibrates, have been approved by the Food and Drug Administration for managing hyperlipidemia. PPARα-specific agonists exert anti-cancer effects in many human cancer types, including glioblastoma (GBM). Recently, we have reported that the hypoxic state in GBM stabilizes hypoxia-inducible factor-1 alpha (HIF-1α), thus contributing to tumor escape from immune surveillance by activating the expression of the pH-regulating protein carbonic anhydrase IX (CA9). In this study, we aimed to study the regulatory effects of the PPARα agonist fibrate on the regulation of HIF-1α expression and its downstream target protein in GBM. Our findings showed that fenofibrate is the high potency compound among the various fibrates that inhibit hypoxia-induced HIF-1α and CA9 expression in GBM. Moreover, fenofibrate-inhibited HIF-1α expression is mediated by HO-1 activation in GBM cells through the AMP-activated protein kinase (AMPK) pathway. In addition, fenofibrate-enhanced HO-1 upregulation activates SIRT1 and leads to subsequent accumulation of SIRT1 in the nucleus, which further promotes HIF-1α deacetylation and inhibits CA9 expression. Using a protein synthesis inhibitor, cycloheximide, we also observed that fenofibrate inhibited HIF-1α protein synthesis. In addition, the administration of the proteasome inhibitor MG132 showed that fenofibrate promoted HIF-1α protein degradation in GBM. Hence, our results indicate that fenofibrate is a useful anti-GBM agent that modulates hypoxia-induced HIF-1α expression through multiple cellular pathways.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine health problem during the childbearing period that seriously affects fertility in females. Fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPARα) agonist, showed beneficial effects in models of endocrine disturbances. Thus, we evaluated the potential therapeutic effect of fenofibrate in experimental PCOS.Rats received oral fenofibrate (300 mg/kg/day) for three weeks following a three-week PCOS induction regimen using oral letrozole (1 mg/kg/day). We determined the changes in body weight, levels of serum testosterone, insulin, anti-Müllerian hormone (AMH), ovarian malondialdehyde (MDA), superoxide dismutase (SOD), and tissue tumor necrosis factor-alpha (TNFα) and CD95 protein expressions. The tissue expression of interleukin-10 (IL10) and PPARα genes was determined.Letrozole-treated rats showed successful induction of PCOS, confirmed by histopathology and significantly increased body weight, testosterone, insulin, AMH, and MDA, and decreased SOD. Ovaries of untreated PCOS rats showed increased TNFα and CD95 and decreased PPARα and IL10 expression. Administration of fenofibrate ameliorated the letrozole-induced PCOS changes.Fenofibrate-mediated amelioration of PCOS in rats is attributed partly to its antioxidant, anti-inflammatory, and anti-apoptotic properties and activation of PPARα.

Fenofibrate (FBR), an oral medication used to treat dyslipidemia, is a ligand of the peroxisome proliferator-activated receptor α (PPARα), a nuclear receptor that regulates the expression of metabolic genes able to control lipid metabolism and food intake. PPARα natural ligands include fatty acids (FA) and FA derivatives such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), known to have anti-inflammatory and anorexigenic activities, respectively. We investigated changes in the FA profile and FA derivatives by HPLC and LC-MS in male C57BL/6J mice fed a standard diet with or without 0.2% fenofibrate (0.2% FBR) for 21 days. Induction of PPARα by 0.2% FBR reduced weight gain, food intake, feed efficiency, and liver lipids and induced a profound change in FA metabolism mediated by parallel enhanced mitochondrial and peroxisomal β-oxidation. The former effects led to a steep reduction of essential FA, particularly 18:3n3, with a consequent decrease of the n3-highly unsaturated fatty acids (HUFA) score; the latter effect led to an increase of 16:1n7 and 18:1n9, suggesting enhanced hepatic de novo lipogenesis with increased levels of hepatic PEA and OEA, which may activate a positive feedback and further sustain reductions of body weight, hepatic lipids and feed efficiency.

This work gives an insight into the process of adsorptive drug loading in silica aerogels from supercritical CO

Multiple Sclerosis (MS) is an autoimmune disease that is characterized by inflammation and demyelination of nerve cells. There is strong evidence that Epstein-Barr virus (EBV), a human herpesvirus infecting B cells, greatly increases the risk of subsequent MS. Intriguingly, EBV not only induces human interleukin-10 but also encodes a homologue of this molecule, which is a key anti-inflammatory cytokine of the immune system. Although EBV-encoded IL-10 (ebvIL-10) has a high amino acid identity with its cellular counterpart (cIL-10), it shows more restricted and partially weaker functionality. We propose that both EBV-induced cIL-10 and ebvIL-10 act in a temporally and functionally coordinated manner helping the pathogen to establish latency in B cells and, at the same time, to balance the function of antiviral T cells. As a result, the EBV load persisting in the immune system is kept at a constant but individually different level (set point). During this immunological tug of war between virus and host, however, MS can be induced as collateral damage if the set point is too high. Here, we discuss a possible role of ebvIL-10 and EBV-induced cIL-10 in EBV-driven pathogenesis of MS.

Parkinson's disease is a neurodegenerative disease, the etiology of which remains unknown, but some likely causes include oxidative stress, mitochondrial dysfunction and neuroinflammation. Peroxisome-proliferator-activated receptor (PPAR) agonists have been studied in animal models of Parkinson's disease and have shown neuroprotective effects. In this study, we aimed to (1) confirm the neuroprotective effects of PPAR-alpha agonist fenofibrate. To this end, male rats received fenofibrate (100 mg/kg) orally for 15 days, 5 days before the intraperitoneal injections of rotenone (2.5 mg/kg for 10 days). After finishing the treatment with rotenone and fenofibrate, animals were subjected to the open field, the forced swim test and the two-way active avoidance task. Subsequently, rats were euthanized for measurement of dopamine and metabolites levels in the striatum and quantification of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra pars compacta (SNpc). In addition, we aimed to (2) evaluate the neuroprotective effects of fenofibrate on the accumulation of α-synuclein aggregates. Here, rats were treated for 5 days with fenofibrate continuing for over 28 days with rotenone. Then, animals were perfused for immunohistochemistry analysis of α-synuclein. The results showed that fenofibrate reduced depressive-like behavior and memory impairment induced by rotenone. Moreover, fenofibrate diminished the depletion of striatal dopamine and protected against dopaminergic neuronal death in the SNpc. Likewise, the administration of fenofibrate attenuated the aggregation of α-synuclein in the SNpc and striatum in the rotenone-lesioned rats. Our study confirmed that fenofibrate exerted neuroprotective effects because parkinsonian rats exhibited reduced behavioral, neurochemical and immunohistochemical changes, and importantly, a lower number of α-synuclein aggregates.

Accumulation of cytotoxic bile acids (BAs) during cholestasis can result in liver failure. Glucuronidation, a phase II metabolism pathway responsible for BA detoxification, is regulated by peroxisome proliferator–activated receptor alpha (PPARα). This study investigates the efficacy of adjunct fenofibrate therapy to up‐regulate BA‐glucuronidation and reduce serum BA toxicity during cholestasis. Adult patients with primary biliary cholangitis (PBC, n = 32) and primary sclerosing cholangitis (PSC, n = 23), who experienced an incomplete response while receiving ursodiol monotherapy (13‐15 mg/kg/day), defined as serum alkaline phosphatase (ALP) ≥ 1.5 times the upper limit of normal, received additional fenofibrate (145‐160 mg/day) as standard of care. Serum BA and BA‐glucuronide concentrations were measured by liquid chromatography–mass spectrometry. Combination therapy with fenofibrate significantly decreased elevated serum ALP (−76%, P, Combination therapy with fenofibrate favorably alters BA‐glucuronidation as a PPARa‐mediated mechanism to reduce elevated serum BAs in patients with PBC and PSC who are incomplete responders to Ursodiol monotherapy. This study also identifies serum BA‐glucuronides and their respective metabolic ratios as indicators of response to therapy. Serum BA‐glucuronides may serve as mechanistically relevant secondary endpoints in clinical trials for PBC and PSC with anti‐cholestatic agents.

Lipid-based formulations, such as self-microemulsifying drug-delivery systems (SMEDDSs), are promising tools for the oral delivery of poorly water-soluble drugs. However, failure to maintain adequate aqueous solubility after coming into contact with gastrointestinal fluids is a major drawback. In this study, we examined the use of a novel cinnamic acid-derived oil-like material (CAOM) that binds drugs with a high affinity through π-π stacking and hydrophobic interactions, as an oil core in a SMEDDS for the oral delivery of fenofibrate in rats. The use of the CAOM in the SMEDDS resulted in an unprecedented enhancement in fenofibrate bioavailability, which exceeded the bioavailability values obtained using SMEDDSs based on corn oil, a conventional triglyceride oil, or Labrasol, an enhancer of intestinal permeation. Further characterization revealed that the CAOM SMEDDS does not alter the intestinal permeability and has no inhibitory activity on P-glycoprotein-mediated drug efflux. The results reported herein demonstrate the strong potential of CAOM formulations as new solubilizers for the efficient and safe oral delivery of drugs that have limited water solubility.

Fenofibrate is currently used as antihyperlipidemic drug, which has a direct effect on lowering cholesterol, triglycerides and LDL (Low-Density Lipids), VLDL (Very Low-Density Lipids) levels along with raising the level of HDL (High-density Lipids) in the blood. It also plays a significant role in insulin resistance metabolic disorder. This drug is mainly used for controlling diseases related to lipids like hypercholesterolemia, severe hypertriglyceridemia and dyslipidaemia. Along with statins, it significantly controls the level of hypercholesterolemia and hypertriglyceridemia. It belongs to the group of drugs called 'Fibrate'. Fenofibrate was patented in 1969. In 1974, it was synthesized as a derivative of clofibrate and launched at the French market. It was marketed in 1975. In 2017, it was available as a generic medicine. Presently this API is being marketed in around 85 countries all over the world. Fenofibrate is a BCS Class-II drug having poor water solubility. The poor aqueous solubility of this drug causes low bioavailability and limited permeability through the GIT membrane. This API degrades at higher temperatures and in a humid environment, with one of the resultant degradation products being fenofibric acid. In the present review, we have discussed the historical development, pharmacology, analytical profile with its physicochemical properties and ongoing research scenario on this API.

The objective of this study is to synthesize a series of sesamol-based phenolic acid derivatives, which were designed by combination principle. The hypolipidemic activity of all these compounds was preliminarily screened by acute hyperlipidemic mice model induced by Triton WR 1339, in which compound T6 exhibited more significant reducing plasma TG and TC than fenofibrate. Compound T6 was also found to obviously decrease TG and TC both in the plasma and hepatic tissue of high-fat-diet-induced hyperlipidemic mice. Moreover, T6 showed hepatoprotective effects, which remarkable amelioration in characteristic liver enzymes was examined and the histopathological observation displayed that compound T6 inhibited lipids accumulation in the hepatic. The levels of PPAR-α receptor related to lipids metabolism in hepatic tissue were upregulated after T6 treatment. Other potent effects of T6 such as antioxidant and anti-inflammatory activity were also observed. On the bases of these findings, compound T6 may serve as an effective hypolipidemic and hepatoprotective agent.

In this study, we hypothesized that deregulation in the maintenance of the pool of coenzyme A (CoA) may play a crucial role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Specific deletion of Acot12 (Acot12−/−), the major acyl-CoA thioesterase, induced the accumulation of acetyl-CoA and resulted in the stimulation of de novo lipogenesis (DNL) and cholesterol biosynthesis in the liver. KEGG pathway analysis suggested PPARα signaling as the most significantly enriched pathway in Acot12−/− livers. Surprisingly, the exposure of Acot12−/− hepatocytes to fenofibrate significantly increased the accumulation of acetyl-CoA and resulted in the stimulation of cholesterol biosynthesis and DNL. Interaction analysis, including proximity-dependent biotin identification (BioID) analysis, suggested that ACOT12 may directly interact with vacuolar protein sorting-associated protein 33A (VPS33A) and play a role in vesicle-mediated cholesterol trafficking and the process of lysosomal degradation of cholesterol in hepatocytes. In summary, in this study, we found that ACOT12 deficiency is responsible for the pathogenesis of NAFLD through the accumulation of acetyl-CoA and the stimulation of DNL and cholesterol via activation of PPARα and inhibition of cholesterol trafficking., Non-alcoholic fatty liver disease: Boosting regulatory enzyme a potential treatment A deficiency in levels of a key enzyme disturbs lipid metabolism in the liver and triggers non-alcoholic fatty liver disease (NAFLD). NAFLD is a common chronic condition in which fat builds up in the liver, heightening the risk of serious health problems. However, the exact mechanisms behind NAFLD are unclear. In experiments on mice, Eun-Jung Jin at Wongwang University in Iksan, South Korea, and co-workers found that deficiencies of an enzyme called ACOT12 can induce NAFLD regardless of dietary intake. The team generated mice without the Acot12 gene, which boosted the biosynthesis of lipid and accumulation of cholesterol in liver cells. Further examination showed that ACOT12 may directly interact with a protein that prompts cholesterol trafficking and degradation. Loss of ACOT12 activated a signaling pathway that inhibited this process. Their findings may inform NAFLD therapies.

BACKGROUND This meta-analysis aimed to evaluate the effectiveness of fibrates in the treatment of pruritus in patients with primary biliary cholangitis (PBC), so as to guide the clinical treatment of such cases. METHODS Searches of the PubMed, Google Scholar, and Cochrane Library databases were performed to identify randomized controlled trials (RCTs) and prospective studies published up to December 2020 that used bezafibrate and fenofibrate as treatments for pruritus in patients with PBC. Data extraction and quality evaluation of the included literature were performed. Review Manager 5.3 software was employed for statistical analysis of the data. RESULTS This meta-analysis included 7 studies, comprising 382 patients with PBC, which assessed the efficacy of bezafibrate and fenofibrate for treating pruritus. The results showed that treatment with fibrates significantly improved pruritus symptoms in patients with PBC [relative risk (RR) =6.52, 95% confidence interval (CI): 3.26-13.06, P

This review aimed to find information about the solubility of the fenofibrate solid dispersion system using PEG 6000. Fenofibrate is an antihyperlipidemic drug that belongs to the Biopharmaceutical Classification System Class II (BCS II) with low solubility. To find information was by conducting a literature search in national and international journals in the last ten years (2010-2020) through websites, namely Google Scholar, Science Direct, NCBI, ResearchGate, and other trusted journals. Several keywords were used as follows: fenofibrate, solid dispersion, PEG 6000, and dissolution rate. The results of several research journals showed that the solid dispersion of fenofibrate using PEG 6000 made by various methods causes a reduction in particle size to increase the solubility and dissolution rate of fenofibrate. The solid dispersions system was made using several methods, namely fusion (melting), solvent evaporation, dropping, and co-grinding, which is a technique used to increase the solubility of a drug. PEG 6000 was chosen as the carrier because it has high hydrophilicity, is non-toxic, inert, economical, has a low melting point, and is dense at melting temperature to withstand crystallization. Thus it can be concluded that the manufacture of solid dispersion of fenofibrate using PEG 6000 and several methods showed the same results, namely an increase in solubility and dissolution rate.

The cardiotoxicity of anticancer drugs such as 5-fluorouracil (5FU) is a major complication that challenges their clinical usefulness. Thus there is a critical need to find new protective drugs to defend against these harmful side effects. Up to now, there have been no studies evaluating the possible cardioprotective effects of fenofibrate (FEN) in 5FU-induced cardiotoxicity. Therefore, we aimed in the current model to evaluate such an effect of FEN and to explore different mechanisms mediating it. We used FEN (25, 50, 100 mg/kg/day) administered orally for 7 days with induction of cardiotoxicity by intraperitoneal (i.p.) injection of 5FU (150 mg/kg) on the fifth day. The current study showed that 5FU succeeded in inducing cardiotoxicity, manifested by significantly elevated levels of cardiac enzymes, tissue malondialdehyde (MDA), interleukin 6 (IL-6), signal transducer and activator of transcription 4 (STAT4), and caspase-3. Furthermore, the 5FU group showed toxic histopathological changes including marked cardiac damage and a significant decrease in reduced glutathione (GSH), total antioxidant capacity (TAC), and peroxisome proliferator-activated receptor alpha (PPARα) expression. FEN reversed 5FU-induced cardiotoxicity by various mechanisms including upregulation of PPARα, inhibition of the IL-6/STAT signaling pathway, and anti-inflammatory, antiapoptotic, and antioxidant properties. FEN demonstrated a significant cardioprotective effect against 5FU-induced cardiac damage.

Here we review literature data on properties of a member of nuclear hormone receptors - peroxisome proliferator-activated receptor-α. It was shown that PPARα was expressed on different cells including dendritic cells, macrophages, B- and T-cells. We discuss structure of natural and synthetic ligands of PPARa, molecular and cellular mechanisms of PPARa regulation of lipid and carbohydrate cellular metabolism. PPARa activity in hepatocytes results in decrease of intracellular concentrations of lipid acids. This leads to reduction of VLDL cholesterol, increase in HDL-cholesterol and decrease in triglycerides in plasma of patients taking PPARα agonists. Modulation of PPARa activity may change multiple biological effects of glucocorticoids (GCS) and insulin resistance. It is assumed that PPARα agonists reduce side effects of GCS and at the same time enhance their anti-inflammatory activity due to transrepression of NF-kB. We analyzed the results of several randomized studies, meta-analyses devoted to assessment of efficacy and safety of PPARa agonist fenofibrate in patients with type 2 diabetes mellitus with high risk of micro- and macrovascular events. The studies showed good safety profile of monotherapy with fibrates as well as of their combinations with statins, ezetimibe. Fibrates reduced not only cardiovascular events but also overall mortality. We present the data on the role of PPARa in control of glucose and lipid metabolism in subpopulations of innate and adaptive immunity cells. The data show that glucose and lipid metabolism play an important role in the fate of cells of innate and adaptive immunity. The metabolic state of lymphocytes has dynamic nature and depends on their functional activity. Transition from dormant cells with relatively low metabolism rate to activated and proliferating cells is accompanied with increase of metabolic demands. This transition is supported with the switch from oxidative metabolism to anaerobic glycolysis (Warburg effect) after antigen recognition by T-cells and B-cells. It was shown that granulocytes, dendritic cells and M1 macrophages were dependent on glucose metabolism during their activation while M2 macrophages were dependent on fatty acids oxidation. In contrast with lymphocytes, activated myeloid cells do not proliferate well but still have increased glycolysis which is necessary for their effector function. It is stressed that modulation of immune cells metabolism via PPARα gives new opportunities to modulate intensity and duration of immune responses in chronic diseases. We analyze studies performed on animal models of some chronic diseases, human patients with rheumatoid arthritis and different phenotypes of osteoarthritis. Most of the studies showed clinical efficacy and pleiotropic effects of PPARα agonists: antiinflammatory, immunomodulating and lipid modulating, primarily reduction of triglycerides and increase in HDL-C. The presented literature data suggest efficacy of PPARα agonists against individual components of polypathies. This could reduce risk of polypharmacy and reduce direct treatment costs. It is not unlikely that the use of PPARα agonists in a patient with multimorbidity could prevent acquiring a new disease. These are merely suggestions and much effort and time is required to perform large-scale randomized controlled studies evaluating new indications for the use of PPARa agonists.

PURPOSE The pursuit of independent living outcomes has been a longstanding emphasis of disability policy, practice, and research. Yet the ways in which the experience of independent living is understood and advanced locally warrants more focused attention. This article describes a collaboration among a regional Center for Independent Living (CIL) and university researchers focused on developing more informed programs and supports to promote independent living for persons with disabilities in their service area. METHOD A total of 75 adults with disabilities attended four "community conversations" during which they provided diverse definitions of independent living and shared a wide range of supports they needed and currently accessed to meet their independent living goals. RESULTS Attendee conversations generated 14 unique dimensions of independent living and 11 categories of independent living supports. Findings align with existing research asserting independent living as a multifaceted construct and extend the literature to include perspectives across a wider range of disability categories. CONCLUSION This study suggests that collaborations among Centers for Independent Living and researchers can be a fruitful context for conducting "needs assessments" and soliciting the perspectives of individuals with disabilities on (a) how they conceptualize independent living and (b) the local services and supports they need to attain their independent living goals.IMPLICATIONS FOR REHABILITATIONCommunity conversations are an efficient and engaging way of soliciting the perspectives of community members with a variety of disabilities.Establishing a planning team fluent in universal design, accessibility options, and local needs is critical to implementing effective community conversations.For Centers for Independent Living (CILs), community conversations offer a valuable approach for obtaining substantive stakeholder input to inform strategic planning.CILS could play an active role in equipping transition-age students with the skills, knowledge, relationships, and linkages needed to attain their independent living goals in early adulthood.

Introduction: Hyperbilirubinemia is a common problem in the neonatal period. Phototherapy is the most important proposed treatments for hyperbilirubinemia, but several drugs along with phototherapy are used with recent advances. Aim: To see the effect of oral fenofibrate on serum bilirubin level in term neonates with unconjugated hyperbilirubinaemia. Methods: This prospective study was carried out in Combined Military Hospital Cumilla from July 2018 to June 2019. Total 60 term and normal birth weight neonates with neonatal jaundice were enrolled in this study. Jaundiced newborns presenting with infection, G6PD deficiency, conjugated bilirubin >2 mg/dl or >15% of total serum bilirubin (TSB) and congenital anomalies were excluded from this study. These neonates were randomly allocated to the Fenofibrate group (30 cases) and Control group (30 cases). Total serum bilirubin was measured every 24 hours till the end of phototherapy and at the time of discharge. Statistical analysis was done using SPSS 22.0 and p

Nonalcoholic fatty liver disease (NAFLD) is regarded as the most common liver disease with no approved therapeutic drug currently. Silymarin, an extract from the seeds of Silybum marianum, has been used for centuries for the treatment of various liver diseases. Although the hepatoprotective effect of silybin against NAFLD is widely accepted, the underlying mechanism and therapeutic target remain unclear. In this study, NAFLD mice caused by methionine-choline deficient (MCD) diet were orally administrated with silybin to explore the possible mechanism and target. To clarify the contribution of peroxisome proliferator-activated receptor α (PPARα), PPARα antagonist GW6471 was co-administrated with silybin to NAFLD mice. Since silybin was proven as a PPARα partial agonist, the combined effect of silybin with PPARα agonist, fenofibrate, was then evaluated in NAFLD mice. Serum and liver samples were collected to analyze the pharmacological efficacy and expression of PPARα and its targets. As expected, silybin significantly protected mice from MCD-induced NAFLD. Furthermore, silybin reduced lipid accumulation via activating PPARα, inducing the expression of liver cytosolic fatty acid-binding protein, carnitine palmitoyltransferase (Cpt)-1a, Cpt-2, medium chain acyl-CoA dehydrogenase and stearoyl-CoA desaturase-1, and suppressing fatty acid synthase and acetyl-CoA carboxylase α. GW6471 abolished the effect of silybin on PPARα signal and hepatoprotective effect against NAFLD. Moreover, as a partial agonist for PPARα, silybin impaired the powerful lipid-lowering effect of fenofibrate when used together. Taken together, silybin protected mice against NAFLD via activating PPARα to diminish lipid accumulation and it is not suggested to simultaneously take silybin and classical PPARα agonists for NAFLD therapy.

Concomitant treatment with drugs that inhibit drug metabolising enzymes and/or transporters, such as commonly prescribed statins and nonsteroidal anti-inflammatory drugs (NSAIDs), has been associated with prolonged drug exposure and increased risk of adverse drug reactions (ADRs) due to drug-drug interactions. The risk is further increased in patients with chronic diseases/comorbidities who are more susceptible because of their genetic setup or external factors. In that light, we present a case of a 46-year-old woman who had been experiencing acute renal and hepatic injury and myalgia over two years of concomitant treatment with diclofenac, atorvastatin, simvastatin/fenofibrate, and several other drugs, including pantoprazole and furosemide. Our pharmacogenomic findings supported the suspicion that ADRs, most notably the multi-organ toxicity experienced by our patient, may be owed to drug-drug-gene interactions and increased bioavailability of the prescribed drugs due to slower detoxification capacity and decreased hepatic and renal elimination. We also discuss the importance of CYP polymorphisms in the biotransformation of endogenous substrates such as arachidonic acid and their modulating role in pathophysiological processes. Yet even though the risks of ADRs related to the above mentioned drugs are substantially evidenced in literature, pre-emptive pharmacogenetic analysis has not yet found its way into common clinical practice.Statini i nesteroidni protuupalni lijekovi (NSAID) učestalo se propisuju, pa i kao konkomitantna terapija. Postoji značajna interindividualna razlika u osjetljivosti na njihove najčešće nuspojave. Rizični čimbenici za razvoj nuspojava tih lijekova mogu biti povezani s lijekom i pacijentom ili s vanjskim čimbenicima. Polifarmacija je česta u kroničnih bolesnika i povećava rizik od razvoja interakcija lijekova. Istodobna primjena lijekovima koji inhibiraju CYP, UGT, ABC i / ili SLC prijenosnike lijekova (ABCB1, ABCG2 i OATP1B1) povezana je s produljenjem bioraspoloživosti lijekova, što rezultira povećanim rizikom od razvoja nuspojava. S tim u vezi, predstavljamo slučaj 46-godišnje žene koja je tijekom dvije godine doživjela akutno oštećenje bubrega i jetre, kao i mialgiju, dok je uzimala diklofenak, atorvastatin, fiksnu kombinaciju simvastatina / fenofibrata istovremeno s nekoliko drugih lijekova, uključujući pantoprazol i furosemid. Analiza dobivenih farmakogenetičkih rezultata te pregled dosadašnjeg znanja u tom području upućuju na zaključke da interakcije lijek-lijekgen mogu produljiti bioraspoloživost primijenjenih lijekova. Mehanizam se argumentirano temelji na sporijoj sposobnosti detoksikacije i smanjenoj eliminaciji putem jetre i bubrega, što rezultira toksičnošću za više organa. Jednako tako, prikazuje se važnost polimorfizama CYP u biotransformaciji endogenih supstrata poput arahidonske kiseline i u njihovoj modulacijskoj ulozi u patofiziološkim procesima. Danas postoje prilično značajni znanstveni dokazi o određenim farmakogenetičkim spoznajama koji rezultiraju povećanim rizikom od razvoja nuspojava za spomenute lijekove, no unatoč tomu, farmakogenetička analiza prije uvođenja lijekova u terapiju još nije uvedena u redovitu kliničku praksu.

This repository contains renal cortical RNA-seq (ZDF and ZDSD rat models) and urinary 1H-NMR data (ZDSD rat model) following a diet-induced weight loss plus medical therapy intervention in rat models of diabetic kidney disease.

A woman in her 30s with gestational diabetes presented at 36 weeks’ gestation with reduced fetal movements and diminishing insulin requirements. In view of her gestation, she was induced and incidentally found to have profound hyponatraemia. Further biochemical investigations confirmed severe hypertriglyceridaemia and hypercholesterolaemia. This raises the possibility of secondary causes such as familial dysbetalipoproteinemia and polygenetic hypertriglyceridaemia. She was successfully managed by aggressive dietary modification. This involved a supervised fast followed by a fat-free diet. A fenofibrate was proposed but declined due to our patient’s wish to breastfeed. Management required considerable input from the multidisciplinary team. Treatment options to consider are aggressive dietary restriction of fat or the addition of a cholesterol-lowering medication, such as a fibrate. In refractory cases, a supervised fast may be required or, in cases where complications have arisen, apheresis. The patient and her baby made a good recovery with no long-lasting health implications.

High-fructose diet is associated with an increased risk of dyslipidemia, metabolic syndrome, and the development of non-alcoholic fatty liver disease (NAFLD) through chronic inflammation. The present study aimed to elucidate the potential benefit of daily consumption of Smallanthus sonchifolius (yacon) roots, rich in fructooligosaccharides (FOS), on the progression to liver fibrosis, in a rat model of NAFLD induced by a high-fructose diet. Male Wistar rats were fed a standard diet (CD, n = 6) or a standard diet plus 10% fructose solution (FD; n = 18). After 20 weeks, FD rats were randomly separated into the following groups (n = 6, each): FD; FD treated with yacon flour (340 mg FOS/body weight; FD + Y) and FD treated with fenofibrate (30 mg/kg body weight; FD + F), for 16 weeks. Daily intake of yacon flour significantly reduced body weight gain, plasma lipid levels, transaminase activities, and improved systemic insulin response in FD rats. In the liver, yacon treatment decreased fructose-induced steatosis and inflammation, and reduced total collagen deposition (64%). Also, yacon decreased TGF-β1 mRNA expression (78%), followed by decreased nuclear localization of p-Smad2/3 in liver tissue. Yacon significantly reduced the expression of α-smooth muscle actin (α-SMA), Col1α1, and Col3α1 mRNAs (85, 44, and 47%, respectively), inhibiting the activation of resident hepatic stellate cells (HSCs). These results suggested that yacon roots have the potential to ameliorate liver damage caused by long-term consumption of a high-fructose diet, being a promising nutritional strategy in NAFLD management.