Saroglitazar suppresses KIM-1 and type IV collagen in high fat diet and low-dose streptozotocin-induced diabetic nephropathy in Wistar rats.

Objectives: Nephropathy is the most common comorbidity linked to T2D. The present study aimed to examine the potential of saroglitazar in the context of a high-fat diet and low-dose streptozotocin-induced diabetic nephropathy in Wistar rats. Materials and Methods: Molecular docking simulation investigations were conducted on the ligand-binding region of type IV collagen and Kidney injury molecule-1 (KIM-1), using saroglitazar and fenofibrate as the subjects. The rats were fed either a conventional rodent diet or a high-fat diet ad libitum for two weeks. Following a two-week period, the rats given an HFD were administered with a low-dose of STZ (35 mg/kg, IP). Rats with experimentally induced diabetes were categorized into five groups: normal control; diabetic control; HFD+STZ+saroglitazar (2 mg/kg); HFD+STZ+saroglitazar (4 mg/kg); HFD+STZ+fenofibrate (100 mg/kg) treated orally for 21 days with continuation on HFD. After 21 days, rats were kept on fasting overnight, blood and urine was acquired for various biochemical analysis. Animals were sacrificed, and kidney tissues were removed for histopathological studies. Results: In-silico investigation showed a substantial affinity between saroglitazar and fenofibrate with KIM-1 and type IV collagen. Saroglitazar produced a significant (P<0.01) reduction in weight of the body, serum blood sugar, albumin, creatinine, and BUN levels. Further, saroglitazar significantly (P<0.01) reduced the KIM-1 and type IV collagen levels in the urine of diabetic rats. Histopathological results showed improvement in tubular degeneration, necrosis, and dilatation of Bowman's space in kidney tissue. Conclusion: Saroglitazar attenuated renal injury by improving renal function in HFD+STZ-induced DN in Wistar rats.

Cardiometabolic benefits of fenofibrate in heart failure related to obesity and diabetes.

BACKGROUND: Heart failure (HF) is a serious and common condition affecting millions of people worldwide, with obesity being a major cause of metabolic disorders such as diabetes and cardiovascular disease. This study aimed to investigate the effects of fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, on the obese- and diabetes-related cardiomyopathy. METHODS AND RESULTS: We used db/db mice and high fat diet-streptozotocin induced diabetic mice to investigate the underlying mechanisms of fenofibrate's beneficial effects on heart function. Fenofibrate reduced fibrosis, and lipid accumulation, and suppressed inflammatory and immunological responses in the heart via TNF signaling. In addition, we investigated the beneficial effects of fenofibrate on HF hospitalization. The Korean National Health Insurance database was used to identify 427,154 fenofibrate users and 427,154 non-users for comparison. During the 4.22-year follow-up, fenofibrate use significantly reduced the risk of HF hospitalization (hazard ratio, 0.907; 95% CI 0.824-0.998). CONCLUSIONS: The findings suggest that fenofibrate may be a useful therapeutic agent for obesity- and diabetes-related cardiomyopathy.

Fenofibrate to prevent amputation and reduce vascular complications in patients with diabetes: FENO-PREVENT.

BACKGROUND: The potential preventive effect of fenofibrate on lower extremity amputation (LEA) and peripheral arterial disease (PAD) in patients with type 2 diabetes (T2D) is not fully elucidated. METHODS: We selected adult patients ≥ 20 years of age with T2D from the Korean National Health Insurance Service Database (2009-2012). The fenofibrate users were matched in a 1:4 ratio with non-users using propensity scores (PS). The outcome variables were a composite of LEA and PAD and the individual components. The risks of outcomes were implemented as hazard ratio (HR) with 95% confidence intervals (CI). For safety issues, the risks of acute kidney injury, rhabdomyolysis and resulting hospitalization were analyzed. RESULTS: A total of 114,920 patients was included in the analysis with a median follow-up duration of 7.6 years (22,984 and 91,936 patients for the fenofibrate user and non-user groups, respectively). After PS matching, both groups were well balanced. The fenofibrate group was associated with significantly lower risks of composite outcome of LEA and PAD (HR 0.81; 95% CI 0.70-0.94), LEA (HR 0.76; 95% CI 0.60-0.96), and PAD (HR 0.81; 95% CI 0.68-0.96). The risk of acute kidney injury, rhabdomyolysis, or hospitalization for these events showed no significant difference between the two groups. Subgroup analyses revealed consistent benefits across age groups, genders, and baseline lipid profiles. CONCLUSIONS: This nationwide population-based retrospective observational study suggests that fenofibrate can prevent LEA and PAD in patients with T2D who are on statin therapy.

Use of fenofibrate as adjuvant to phototherapy in unconjugated neonatal hyperbilirubinemia: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Most neonates have neonatal jaundice, with 5-15% requiring phototherapy. Although phototherapy is beneficial, it can potentially extend hospital stays and cause harm. This study's purpose was to analyze the effects of fenofibrate and phototherapy on total serum bilirubin (TSB) levels at 24 and 48 hours (primary outcome) after intervention. Furthermore, the phototherapy duration and adverse events were also of interest (secondary outcome). METHODS: The study protocol was registered in the PROSPERO database. Articles were searched on EMBASE, PubMed, Cochrane Library, and Google Scholar. Study selection was done following PRISMA and risk of bias studies were conducted. The Review Manager 5.4 was used for the meta-analysis. RESULTS: Nine studies, including 610 newborns, were identified and included in the meta-analysis. This meta-analysis discovered a significant change in TSB levels at 24 hours after intervention (mean difference (MD) -0.96 (95% CI -1.09, -0.83), p <  0.00001) with low heterogeneity and at 48 hours after intervention (MD -1.75 (95% CI -2.26, -1.24), p <  0.00001) with high heterogeneity. Significant shortening of phototherapy duration was observed in the interventional group (MD -15.28 (95% CI -20.65, -9.90), p <  0.00001) with high heterogeneities. One of the nine studies reported a non-significant occurrence of abdominal distension and diarrhea in the fenofibrate group. CONCLUSION: Fenofibrate might be applied as an adjuvant in unconjugated neonatal hyperbilirubinemia to reduce the average total serum bilirubin and shorten the length of phototherapy.

Amorphous stabilization of BCS II drugs using mesoporous silica.

This study aimed to investigate the amorphous stabilization of BCS Class II drugs using mesoporous silica as a carrier to produce amorphous solid dispersions. Ibuprofen, fenofibrate, and budesonide were selected as model drugs to evaluate the impact of molecular weight and partition coefficient on the solid state of drug-loaded mesoporous silica (MS) particles. The model drugs were loaded into three grades of MS, SYLYSIA SY730, SYLYSIA SY430, and SYLYSIA SY350, with pore diameters of 2.5 nm, 17 nm, and 21 nm, respectively, at 1:1, 2:1, and 3:1, carrier to drug ratios, and three different loading concentrations using solvent immersion and spray drying techniques. Differential scanning calorimetry (DSC) thermograms of SY430 and SY350 samples exhibited melting point depressions indicating constricted crystallization inside the pores, whereas SY730 samples with melting points matching the pure API may be a result of surface crystallization. Powder x-ray diffraction (PXRD) diffractograms showed all crystalline samples matched the diffraction patterns of the pure API indicating no polymorphic transitions and all 3:1 ratio samples exhibited amorphous halo profiles. Response surface regression analysis and Classification and Regression Tree (CART) analysis suggest carrier to drug ratios, followed by molecular weight, have the most significant impact on the crystallinity of a drug loaded into MS particles.

Amorphous Solid Dispersions: Implication of Method of Preparation and Physicochemical Properties of API and Excipients.

The present study investigated the effect of different polymers and manufacturing methods (hot melt extrusion, HME, and spray drying, SD) on the solid state, stability and pharmaceutical performance of amorphous solid dispersions. In the present manuscript, a combination of different binary amorphous solid dispersions containing 20% and 30% of drug loadings were prepared using SD and HME. The developed solid-state properties of the dispersions were evaluated using small- and wide-angle X-ray scattering (WAXS) and modulated differential scanning calorimetry (mDSC). The molecular interaction between the active pharmaceutical ingredients (APIs) and polymers were investigated via infrared (IR) and Raman spectroscopy. The in vitro release profile of the solid dispersions was also evaluated to compare the rate and extend of drug dissolution as a function of method of preparation. Thereafter, the effect of accelerated stability conditions on the physicochemical properties of the solid dispersions were also evaluated. The results demonstrated higher stability of Soluplus® (SOL) polymer-based solid dispersions as compared to hydroxypropyl methylcellulose (HPMC)-based solid dispersions. Moreover, the stability of the solid dispersions was found to be higher in the case of API having high glass transition temperature (Tg) and demonstrated higher interaction with the polymeric groups. Interestingly, the stability of the melt-extruded dispersions was found to be slightly higher as compared to the SD formulations. However, the down-processing of melt-extruded strands plays critical role in inducing the API crystal nuclei formation. In summary, the findings strongly indicate that the particulate properties significantly influence the performance of the product.

Development of Orodispersible Tablets with Solid Dispersions of Fenofibrate and Co-Processed Mesoporous Silica for Improved Dissolution.

Poor water solubility is an important challenge in the development of oral patient-friendly solid dosage forms. This study aimed to prepare orodispersible tablets with solid dispersions of a poorly water-soluble drug fenofibrate and a co-processed excipient consisting of mesoporous silica and isomalt. This co-processed excipient, developed in a previous study, exhibited improved flow and compression properties compared to pure silica while maintaining a high specific surface area for drug adsorption. Rotary evaporation was used to formulate solid dispersions with different amounts of fenofibrate, which were evaluated for solid state properties and drug release. The solid dispersion with 30% fenofibrate showed no signs of crystallinity and had a significantly improved dissolution rate, making it the optimal sample for formulation or orodispersible tablets. The aim was to produce tablets with minimal amounts of additional excipients while achieving a drug release profile similar to the uncompressed solid dispersion. The compressed formulations met the requirements for orodispersible tablets in terms of disintegration time, and the drug release from best formulation approximated the profile of uncompressed solid dispersion. Future research should focus on reducing the disintegration time and tablet size to enhance patient acceptability further.

Haptoglobin phenotype and levels in type 2 diabetes and effects of fenofibrate.

AIMS/HYPOTHESIS: In diabetes haptoglobin (Hp) 2 vs Hp 1 allelic product is associated with cardiac and renal complications. Few studies report both Hp phenotype and Hp levels. In a Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial substudy we evaluated the Hp phenotype, Hp levels, and fenofibrate effects. MATERIALS AND METHODS: In 480 adults with type 2 diabetes (T2D) the Hp phenotype was assessed and the Hp level quantified (both using ELISAs assays) in plasma from baseline, after 6 weeks of fenofibrate, and (in n = 200) at 2 years post-randomization to fenofibrate or placebo. RESULTS: The Hp phenotypes 1-1, 2-1, and 2-2 frequencies were 15%, 49%, and 36%, respectively. Baseline Hp levels differed by phenotype (P < 0.0001) and decreased (median 21%) after 6 weeks fenofibrate in all phenotypes (adjusted mean (95% CI): -0.27 (-0.32, -0.23) mg/mL in Hp 1-1, -0.29 (-0.31, -0.27) mg/mL in Hp 2-1 and -0.05 (-0.07, -0.02) mg/mL in Hp 2-2 (P = 0.005 and P = 0.055 vs Hp 1-1 and Hp 2-1, respectively)). At 2 years post-randomization the Hp levels in the placebo group had returned to baseline, whilst the fenofibrate-group levels remained similar to the 6 week levels. CONCLUSIONS: In type 2 diabetes, Hp levels differ by Hp phenotype and are decreased by fenofibrate in all phenotypes, but the effect is diminished in Hp 2-2.

A facile synthesis of 2-(4-((4-chlorophenyl)(hydroxy)methyl) phenoxy)-2-methylpropanoic acid: Metabolite of anti-hyperlipidemic drug Fenofibrate.

Synthesis and characterization of drug metabolites has emerged as an important area of research in consideration to the significant contribution of studies on metabolites in drug research. The present work comprises synthesis of 2-(4-((4-chlorophenyl)(hydroxy)methyl) phenoxy)-2-methylpropanoic acid, a metabolite of anti-hyperlipidemic drug fenofibrate. The desired compound was prepared by two different synthetic routes. The ketone group of fenofibric acid was reduced using sodium borohydride in one route whereas the hydrolysis of isopropyl ester of the reduced fenofibrate was achieved by the mild alkaline hydrolysis in the other path. Both the ways of synthesis furnished the desired compound in excellent yield and purity. The new synthetic congener was characterized by spectroscopic methods.

Fenofibrate and risk of end-stage renal disease: A nationwide cohort study.

AIM: Previous studies have shown that fenofibrate improves outcomes such as albuminuria and estimated glomerular filtration rate decline. We hypothesize that fenofibrate has renoprotective effects and prevents or delays the development of end-stage renal disease. The objective of this study is to investigate the risk of incident end-stage renal disease in relation to fenofibrate treatment in patients who are already taking statins. MATERIALS AND METHODS: We performed a nationwide population-based cohort study using data from the Korea National Health Information Database from 2010 to 2017. Among adults using statins, 413 715 fenofibrate users were compared with 413 715 fenofibrate non-users after 1:1 age, sex and triglyceride matching. The endpoint of this study was incident end-stage renal disease. RESULTS: During a median 3.96-year follow-up, the incidence per 1000 person years of end-stage renal disease was lower in fenofibrate users than in fenofibrate non-users (0.885 vs. 0.960, p < 0.0001). The hazard ratio for end-stage renal disease was lower (0.763, 95% confidence interval 0.710-0.821) in fenofibrate users. This association was significant in patients with hypertension, proteinuria and an estimated glomerular filtration rate <60 mL/min/1.732. CONCLUSIONS: Fenofibrate use in patients taking statins with either hypertension, proteinuria, or decreased estimated glomerular filtration rate is associated with a low risk of incident end-stage renal disease. To confirm the renoprotective effect of fenofibrate in chronic kidney disease, a randomized controlled trial is warranted.

Fenofibrate-promoted hepatomegaly and liver regeneration are PPARα-dependent and partially related to the YAP pathway.

Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, is widely prescribed for hyperlipidemia management. Recent studies also showed that it has therapeutic potential in various liver diseases. However, its effects on hepatomegaly and liver regeneration and the involved mechanisms remain unclear. Here, the study showed that fenofibrate significantly promoted liver enlargement and regeneration post-partial hepatectomy in mice, which was dependent on hepatocyte-expressed PPARα. Yes-associated protein (YAP) is pivotal in manipulating liver growth and regeneration. We further identified that fenofibrate activated YAP signaling by suppressing its K48-linked ubiquitination, promoting its K63-linked ubiquitination, and enhancing the interaction and transcriptional activity of the YAP-TEAD complex. Pharmacological inhibition of YAP-TEAD interaction using verteporfin or suppression of YAP using AAV Yap shRNA in mice significantly attenuated fenofibrate-induced hepatomegaly. Other factors, such as MYC, KRT23, RAS, and RHOA, might also participate in fenofibrate-promoted hepatomegaly and liver regeneration. These studies demonstrate that fenofibrate-promoted liver enlargement and regeneration are PPARα-dependent and partially through activating the YAP signaling, with clinical implications of fenofibrate as a novel therapeutic agent for promoting liver regeneration.

Fenofibrate's impact on cardiovascular risk in patients with diabetes: a nationwide propensity-score matched cohort study.

BACKGROUND: The beneficial effects of fenofibrate on atherosclerotic cardiovascular disease (ASCVD) outcomes in patients with diabetes and statin treatment are unclear. We investigated the effects of fenofibrate on all-cause mortality and ASCVD in patients with diabetes, high triglyceride (TG) levels and statin treatment. METHODS: We performed a nationwide propensity-score matched (1:1) cohort study using data from the National Health Information Database in the Republic of Korea from 2010 to 2017. The study included 110,723 individuals with diabetes, TG levels ≥ 150 mg/dL, and no prior diagnoses of ASCVD who used statins and fenofibrate, and an equal matched number of similar patients who used statins alone (control group). The study outcomes included newly diagnosed myocardial infarction (MI), stroke, both (MI and/or stroke), and all-cause mortality. RESULTS: Over a mean 4.03-year follow-up period, the hazard ratios (HR) for outcomes in the fenofibrate group in comparison to the control group were 0.878 [95% confidence interval (CI) 0.827-0.933] for MI, 0.901 (95% CI 0.848-0.957) for stroke, 0.897 (95% CI 0.858-0.937) for MI and/or stroke, and 0.716 (95% CI 0.685-0.749) for all-cause death. These beneficial effects of fenofibrate were consistent in the subgroup with TG 150-199 mg/dL but differed according to low-density lipoprotein cholesterol (LDL-C) levels. CONCLUSION: In this nationwide propensity-score matched cohort study involving individuals with diabetes and TG ≥ 150 mg/dL, the risk of all-cause death and ASCVD was significantly lower with fenofibrate use in conjunction with statin treatment compared to statin treatment alone. However, this finding was significant only in individuals with relatively high LDL-C levels.

Fenofibrate and diabetic retinopathy.

Background: Diabetic retinopathy (DR), a sight-threatening ocular complication of diabetes mellitus, is one of the main causes of blindness in the working-age population. Dyslipidemia is a potential risk factor for the development or worsening of DR, with conflicting evidence in epidemiological studies. Fenofibrate, an antihyperlipidemic agent, has lipid-modifying and pleiotropic (non-lipid) effects that may lessen the incidence of microvascular events. Methods: Relevant studies were identified through a PubMed/MEDLINE search spanning the last 20 years, using the broad term "diabetic retinopathy" and specific terms "fenofibrate" and "dyslipidemia". References cited in these studies were further examined to compile this mini-review. These pivotal investigations underwent meticulous scrutiny and synthesis, focusing on methodological approaches and clinical outcomes. Furthermore, we provided the main findings of the seminal studies in a table to enhance comprehension and comparison. Results: Growing evidence indicates that fenofibrate treatment slows DR advancement owing to its possible protective effects on the blood-retinal barrier. The protective attributes of fenofibrate against DR progression and development can be broadly classified into two categories: lipid-modifying effects and non-lipid-related (pleiotropic) effects. The lipid-modifying effect is mediated through peroxisome proliferator-activated receptor-α activation, while the pleiotropic effects involve the reduction in serum levels of C-reactive protein, fibrinogen, and pro-inflammatory markers, and improvement in flow-mediated dilatation. In patients with DR, the lipid-modifying effects of fenofibrate primarily involve a reduction in lipoprotein-associated phospholipase A2 levels and the upregulation of apolipoprotein A1 levels. These changes contribute to the anti-inflammatory and anti-angiogenic effects of fenofibrate. Fenofibrate elicits a diverse array of pleiotropic effects, including anti-apoptotic, antioxidant, anti-inflammatory, and anti-angiogenic properties, along with the indirect consequences of these effects. Two randomized controlled trials-the Fenofibrate Intervention and Event Lowering in Diabetes and Action to Control Cardiovascular Risk in Diabetes studies-noted that fenofibrate treatment protected against DR progression, independent of serum lipid levels. Conclusions: Fenofibrate, an oral antihyperlipidemic agent that is effective in decreasing DR progression, may reduce the number of patients who develop vision-threatening complications and require invasive treatment. Despite its proven protection against DR progression, fenofibrate treatment has not yet gained wide clinical acceptance in DR management. Ongoing and future clinical trials may clarify the role of fenofibrate treatment in DR management.

Promotion of maturation of human pluripotent stem cell-derived cardiomyocytes via treatment with the peroxisome proliferator-activated receptor alpha agonist Fenofibrate.

As research on in vitro cardiotoxicity assessment and cardiac disease modeling becomes more important, the demand for human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is increasing. However, it has been reported that differentiated hPSC-CMs are in a physiologically immature state compared to in vivo adult CMs. Since immaturity of hPSC-CMs can lead to poor drug response and loss of acquired heart disease modeling, various approaches have been attempted to promote maturation of CMs. Here, we confirm that peroxisome proliferator-activated receptor alpha (PPARα), one of the representative mechanisms of CM metabolism and cardioprotective effect also affects maturation of CMs. To upregulate PPARα expression, we treated hPSC-CMs with fenofibrate (Feno), a PPARα agonist used in clinical hyperlipidemia treatment, and demonstrated that the structure, mitochondria-mediated metabolism, and electrophysiology-based functions of hPSC-CMs were all mature. Furthermore, as a result of multi electrode array (MEA)-based cardiotoxicity evaluation between control and Feno groups according to treatment with arrhythmia-inducing drugs, drug response was similar in a dose-dependent manner. However, main parameters such as field potential duration, beat period, and spike amplitude were different between the 2 groups. Overall, these results emphasize that applying matured hPSC-CMs to the field of preclinical cardiotoxicity evaluation, which has become an essential procedure for new drug development, is necessary.

Reno-protective effect of fenofibrate and febuxostat against vancomycin-induced acute renal injury in rats: Targeting PPARγ/NF-κB/COX-II and AMPK/Nrf2/HO-1 signaling pathways.

BACKGROUND: Vancomycin (VCM) is used clinically to treat serious infections caused by multi-resistant Gram-positive bacteria, although its use is severely constrained by nephrotoxicity. This study investigated the possible nephroprotective effect of febuxostat (FX) and/or fenofibrate (FENO) and their possible underlying mechanisms against VCM-induced nephrotoxicity in a rat model. METHODS: Male Wistar rats were randomly allocated into five groups; Control, VCM, FX, FENO, and combination groups. Nephrotoxicity was evaluated histopathologically and biochemically. The oxidative stress biomarkers (SOD, MDA, GSH, total nitrite, GPx, MPO), the apoptotic marker, renal Bcl-2 associated X protein (Bax), and inflammatory and kidney injury markers (IL-1ß, IL-6, TNF-α, Nrf2, OH-1, kappa-light-chain-enhancer of activated B cells (NF-κB), NADPH oxidase, Kim-1, COX-II, NGAL, Cys-C were also evaluated. RESULTS: VCM resulted in significant elevation in markers of kidney damage, oxidative stress, apoptosis, and inflammatory markers. Co-administration of VCM with either/or FX and FENO significantly mitigated nephrotoxicity and associated oxidative stress, inflammatory and apoptotic markers. In comparison to either treatment alone, a more notable improvement was observed with the FX and FENO combination regimen. CONCLUSION: Our findings show that FX, FENO, and their combination regimen have a nephroprotective impact on VCM-induced kidney injury by suppressing oxidative stress, apoptosis, and the inflammatory response. Renal recovery from VCM-induced injury was accomplished by activation of Nrf2/HO-1 signaling and inhibition of NF-κB expression. This study highlights the importance of FX and FENO as effective therapies for reducing nephrotoxicity in VCM-treated patients.

Fenofibrate reduces cardiac remodeling by mitochondrial dynamics preservation in a renovascular model of cardiac hypertrophy.

Fenofibrate, a PPAR-α agonist clinically used to lower serum lipid levels, reduces cardiac remodeling and improves cardiac function. However, its mechanism of action is not completely elucidated. In this study we examined the effect of fenofibrate on mitochondria in a rat model of renovascular hypertension, focusing on mediators controlling mitochondrial dynamics and autophagy. Rats with two-kidney one-clip (2K1C) hypertension were treated with fenofibrate 150 mg/kg/day (2K1C-FFB) or vehicle (2K1C-VEH) for 8 weeks. Systolic blood pressure and cardiac functional were in-vivo assessed, while cardiomyocyte size and protein expression of mediators of cardiac hypertrophy and mitochondrial dynamics were ex-vivo examined by histological and Western blot analyses. Fenofibrate treatment counteracted the development of hypertension and the increase of left ventricular mass, relative wall thickness and cross-sectional area of cardiomyocytes. Furthermore, fenofibrate re-balanced the expression Mfn2, Drp1 and Parkin, regulators of fusion, fission, mitophagy respectively. Regarding autophagy, the LC3-II/LC3-I ratio was increased in 2K1C-VEH and 2K1C-FFB, whereas the autophagy was increased only in 2K1C-FFB. In cultured H9C2 cardiomyoblasts, fenofibrate reversed the Ang II-induced mRNA up-regulation of hypertrophy markers Nppa and Myh7, accumulation of reactive oxygen species and depolarization of the mitochondrial membrane exerting protection mediated by up-regulation of the Uncoupling protein 2. Our results indicate that fenofibrate acts directly on cardiomyocytes and counteracts the pressure overload-induced cardiac maladaptive remodeling. This study reveals a so far hidden mechanism involving mitochondrial dynamics in the beneficial effects of fenofibrate, support its repurposing for the treatment of cardiac hypertrophy and provide new potential targets for its pharmacological function.

Assessment of bone tissue cytoarchitectonics by 2D 1H NMR relaxometry maps.

Bone is a complex tissue that fulfills the role of a resistance structure. This quality is most commonly assessed by bone densitometry, but bone strength may not only be related to bone mineral density but also to the preservation of bone cytoarchitectonics. The study included two groups of rats, ovariectomized and non-ovariectomized. Each group was divided into three batches: control, simvastatin-treated, and fenofibrate-treated. In the ovariectomized group, hypolipidemic treatment was instituted at 12 weeks post ovariectomy. One rat from each of the 6 batches was sacrificed 8 weeks after the start of treatment in the group. The experimental study was performed using a Bruker Minispec mq 20 spectrometer operating at a frequency of 20 MHz, subsequently also performed by 1H T2-T2 molecular exchange maps. The results were represented by T2-T2 molecular exchange maps that showed, comparatively, both pore size and their interconnectivity at the level of the femoral epiphysis, being able to evaluate both the effect of estrogen on bone tissue biology and the effect of the lipid-lowering medication, simvastatin, and fenofibrate, in both the presence and absence of estrogen. T2-T2 molecular exchange maps showed that the absence of estrogen results in an increase in bone tissue pore size and interconnectivity. In the presence of estrogen, lipid-lowering medication, both simvastatin and fenofibrate alter bone tissue cytoarchitectonics by reducing pore interconnectivity. In the absence of estrogen, fenofibrate improves bone tissue cytoarchitectonics, the T2-T2 molecular exchange map being similar to that of non-osteoporotic bone tissue.

Designing starch-based fenofibrate formulations using the melting method.

Fenofibrate (FNF) is used to treat hyperlipidemia. However, FNF is a poorly water-soluble drug, and the dosage of commercial products is relatively high at 160 mg in a Lipidil® tablet. Therefore, this study aimed to develop an FNF-solid dispersion (SD) that solubilizes and stabilizes FNF. The melting method that uses the low melting point of FNF was employed. The dissolution percentage of FNF in the optimal formulation (SD2) increased by 1.2-, 1.3-, and 1.3-fold at 5 min compared to that of Lipidil® and increased by 2.0-, 2.1-, and 2.0-fold compared to the pure FNF in pH 1.2 media, distilled water, and pH 6.8 buffer, which included 0.025 M sodium lauryl sulfate, respectively. The SD2 formulation showed a dissolution percentage of nearly 100 % in all dissolution media after 60 min. The physicochemical properties of the SD2 formulation exhibited slight changes in the melting point and crystallinity of FNF. Moreover, the stability of the SD2 formulation was maintained for six months. In particular, it was challenging to secure stability when starch#1500 was excluded from the SD2 formulation. In conclusion, the dissolution percentage of FNF in the SD2 formulation was improved owing to the weak binding force between FNF and the excipients, stability was secured, and favorable results are expected in future animal experiments.

Fenofibrate ameliorates nitroglycerin-induced migraine in rats: Role of CGRP/p-CREB/P2X3 and NGF/PKC/ASIC3 signaling pathways.

Migraine, a debilitating neurological condition, significantly affects patients' quality of life. Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPAR-α) agonist approved for managing dyslipidemia, has shown promise in treating neurological disorders. Therefore, this study aims to investigate the protective effects of fenofibrate against nitroglycerin (NTG)-induced chronic migraine in rats. Migraine was induced in rats by administering five intermittent doses of NTG (10 mg/kg, i. p.) on days 1, 3, 5, 7, and 9. Rats were treated with either topiramate (80 mg/kg/day, p. o.), a standard drug, or fenofibrate (100 mg/kg/day, p. o.) from day 1-10. Fenofibrate significantly improved mechanical and thermal hypersensitivity, photophobia, and head grooming compared to topiramate. These effects were associated with reduced serum levels of nitric oxide (NO), calcitonin gene-related peptide (CGRP), and pituitary adenylate cyclase-activating polypeptide (PACAP). Furthermore, fenofibrate down-regulated c-Fos expression in the medulla and medullary pro-inflammatory cytokine contents. Additionally, fenofibrate attenuated NTG-induced histopathological changes in the trigeminal ganglia and trigeminal nucleus caudalis. These effects were associated with the inhibition of CGRP/p-CREB/purinergic 2X receptor 3 (P2X3) and nerve growth factor (NGF)/protein kinase C (PKC)/acid-sensing ion channel 3 (ASIC3) signaling pathways. This study demonstrates that fenofibrate attenuated NTG-induced migraine-like signs in rats. These effects were partially mediated through the inhibition of CGRP/p-CREB/P2X3 and NGF/PKC/ASIC3 signaling pathways. The present study supports the idea that fenofibrate could be an effective candidate for treating migraine headache without significant adverse effects. Future studies should explore its clinical applicability.

Investigating the Influence of Processing Conditions on Dissolution and Physical Stability of Solid Dispersions with Fenofibrate and Mesoporous Silica.

The study aimed to enhance the solubility of the poorly water-soluble drug, fenofibrate, by loading it onto mesoporous silica, forming amorphous solid dispersions. Solid dispersions with 30% fenofibrate were prepared using the solvent evaporation method with three solvents (ethyl acetate, acetone, and isopropanol) at different temperatures (40 °C, boiling point temperature). Various characteristics, including solid-state properties, particle morphology, and drug release, were evaluated by different methods and compared to a pure drug and a physical mixture of fenofibrate and silica. Results revealed that higher solvent temperatures facilitated complete amorphization and rapid drug release, with solvent choice having a lesser impact. The optimal conditions for preparation were identified as ethyl acetate at boiling point temperature. Solid dispersions with different fenofibrate amounts (20%, 25%, 35%) were prepared under these conditions. All formulations were fully amorphous, and their dissolution profiles were comparable to the formulation with 30% fenofibrate. Stability assessments after 8 weeks at 40 °C and 75% relative humidity indicated that formulations prepared with ethyl acetate and at 40 °C were physically stable. Interestingly, some formulations showed improved dissolution profiles compared to initial tests. In conclusion, mesoporous silica-based solid dispersions effectively improved fenofibrate dissolution and demonstrated good physical stability if prepared under appropriate conditions.