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Alcohol Use Disorder (AUD) is a chronic relapsing disorder affecting an estimated 283 million individuals worldwide, with substantial health and economic consequences. Peroxisome proliferator-activated receptors (PPARs), particularly PPAR-α and PPAR-γ, have shown promise in preclinical studies as potential therapeutic targets for AUD. In this human laboratory study, we aimed to translate preclinical findings on the PPAR-α agonist fenofibrate to a human population with current AUD. We hypothesized that, relative to placebo, fenofibrate at the highest FDA-approved dose of 145 mg/d would attenuate responsiveness to in vivo alcohol cues in the lab and reduce drinking under natural conditions. However, the results did not show significant differences in craving and alcohol consumption between the fenofibrate and placebo groups. Reverse translational studies in rodent models confirmed the lack of fenofibrate effect at human-equivalent doses. These findings suggest that inadequate translation of drug dose from rodents to humans may account for the lack of fenofibrate effects on alcohol craving and consumption in humans with AUD. The results highlight the need for new brain-penetrant PPAR-α agonists to adequately test the therapeutic potential of PPAR-α agonists for AUD, and the importance of reverse translational approaches and selection of human-equivalent doses in drug development.

Introduction Materials and Methods Results Conclusion Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions and repetitive behaviors. This study examines the effects of fenofibrate on a propionic acid (PPA)‐induced rat model of ASD, focusing on behavioral changes, inflammatory markers, and histological findings.Thirty male Wistar rats were divided into three groups: a control group, a group receiving PPA and saline, and a group treated with PPA and fenofibrate for 15 days. Behavioral assessments, including the three‐chamber sociability test, open‐field test, and passive avoidance learning, were conducted. Biochemical analyses measured TNF‐α, NGF, IL‐17, IL‐2, and galectin‐3 levels in brain tissues. Histological evaluations focused on Purkinje neuron counts in the cerebellum and neuronal changes in the CA1 and CA3 regions of the hippocampus, along with glial fibrillary acidic protein (GFAP) levels.Fenofibrate treatment significantly improved behavioral outcomes, reducing autism‐like behaviors compared to the PPA/saline group. Biochemically, the PPA/saline group showed elevated levels of malondialdehyde, TNF‐α, IL‐2, IL‐17, and galectin‐3, which were reduced following fenofibrate treatment. Histologically, the PPA/saline group exhibited fewer, dysmorphic Purkinje neurons and increased glial activity in the CA1 region, both of which were ameliorated by fenofibrate treatment.Fenofibrate shows promise in mitigating autism‐like behaviors in a rat model of ASD, likely due to its antioxidative and neuroprotective properties, which contribute to preserving neuronal integrity and reducing inflammation. [ABSTRACT FROM AUTHOR]

Pharmacological preconditioning is an alternative to protect the heart against the consequences of damage from ischemia/reperfusion (I/R). It is based on the administration of specific drugs that imitate the effect of ischemic preconditioning (IPC). Peroxisomal proliferator-activated receptors (PPARs) can prevent apoptosis in pathologies such as I/R and heart failure. Therefore, our objective was to determine if the stimulation of PPARα with fenofibrate (feno) decreases the apoptotic process induced by hypoxia/reoxygenation (HR), high glucose (HG), and HR/HG. For that purpose, cardiomyocyte cultures were divided into the following groups: Group 1—control (Ctrl); Group 2—HR; Group 3—HR + 10 μM feno; Group 4—HG, (25 mM glucose); Group 5—HG + feno; Group 6—HR/HG, and Group 7—HR/HG + feno. Our results indicate that cell viability decreases in neonatal cardiomyocytes undergoing HR, HG, and their combination, while feno improved cell viability. Feno treatment decreased apoptosis compared with HG-, HR-, or HG/HR-vehicle-treated. Nuclear- and mitochondrial-apoptosis markers increased in neonatal cardiomyocytes from HR, HG, and HR/HG; while the cytotoxicity decreased in cells treated with feno. In addition, the expression of Bax, Bad, and caspase 9 decreased due to feno, while 14-3-3ɛ and Bcl2 were increased. Inner mitochondrial cytochrome C increased with feno in every condition, as well as mitochondrial activity. Feno treatment prevented injury in the ultrastructure and in the mitochondrial membranes. Thus, our results suggest that feno decreases apoptosis in neonatal cardiomyocytes, improving the ultrastructure of mitochondria in the pathological conditions studied. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective(s): 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. [ABSTRACT FROM AUTHOR]

BACKGROUND: Oxidative injury is considered to be one of the important factors of cerebral ischemia-reperfusion injury. Superoxide dismutase 2 (SOD2) is a key mitochondrial antioxidant molecule, and fenofibrate can regulate the expression of SOD2 by activating peroxisome proliferator-activated receptor α.OBJECTIVE: To explore whether the mechanism of fenofibrate in the treatment of cerebral ischemia-reperfusion injury depends on the expression of SOD2. METHODS: The TALENs system was used to construct SOD2 transgenic mice. The transgenic mice were genotyped by PCR and DNA sequencing techniques. The expression of SOD2 protein in transgenic mice was detected by western blot assay. Wild-type and SOD2 transgenic mice were randomly divided into four groups: wild-type control group (n=6), wild-type fenofibrate group (n=6), SOD2 transgenic control group (n=5) and SOD2 transgenic fenofibrate group (n=5). A mouse model of middle cerebral artery occlusion was prepared using the suture-occlusion method. After 90 minutes of ischemia, the thread was removed to reperfuse cerebral blood flow for 30 minutes. A cerebral blood flow monitor was used to monitor local cerebral blood flow. Brain tissue slices were taken for 2,3,5-triphenyltetrazolium chloride staining to analyze the situation of cerebral infarction in each group. RESULTS AND CONCLUSION: After PCR and DNA sequencing analysis, nine SOD2+/+ transgenic mice were successfully constructed. After cerebral ischemiareperfusion, the wild-type fenofibrate group showed partial recovery of cerebral blood flow and significantly reduced cerebral infarction volume compared with the wild-type control group (P < 0.001). There was no significant difference in cerebral blood flow and cerebral infarction volume between the SOD2 transgenic fenofibrate group and the SOD2 transgenic control group. The SOD2 transgenic control was superior to the wild-type control group in terms of improving cerebral blood flow and cerebral infarction (P < 0.001). There were also no significant differences in cerebral blood flow and cerebral infarction volume between the wild-type fenofibrate group and the SOD2 transgenic control group and between the wild-type fenofibrate group and the SOD2 transgenic fenofibrate group. To conclude, the expression of SOD2 is one of the mechanisms of fenofibrate in the treatment of cerebral ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

Background: Lipoprotein glomerulopathy is an infrequent glomerular disorder that culminates in nephrotic syndrome and often progresses to kidney failure. Whereas most patients have been reported in Japan and China, limited reports have been documented outside these regions. This patient represents the first report of lipoprotein glomerulopathy in Pakistan. Case Presentation: A 25-year-old male patient, hypertensive for 2 years, presented with progressive body edema, frothy urine, and fatigue. Examination revealed elevated blood pressure, bilateral pedal edema, and positive shifting dullness. Laboratory results showed significant proteinuria and elevated cholesterol and triglyceride levels. Renal biopsy revealed enlarged glomeruli with a dilated capillary lumen filled with pale-staining mesh-like material "lipoprotein thrombi." Mild tubular atrophy and interstitial inflammation were observed. No interstitial fibrosis was evident. Electron microscopy detailed the lipoprotein thrombi with lipid granules and vacuoles of various sizes. A diagnosis of lipoprotein glomerulopathy was rendered. Treatment with fenofibrate, rosuvastatin, and captopril led to notable improvements in symptoms, blood pressure, and lipid levels during a 6-month follow-up. Subsequent biopsy showed complete resolution of the lipoprotein thrombi and a significant reduction in subendothelial granular densities. However, the flocculent subendothelial material persisted to some extent despite the complete resolution of lipoprotein thrombi. Conclusion: This report underscores the rarity of lipoprotein glomerulopathy in Pakistan and contributes valuable insights into its histopathologic features and global epidemiology. This unique instance aims to raise awareness among healthcare professionals, aiding in improved recognition of this rare entity. The favorable response to fenofibrate treatment underscores its effectiveness in managing lipoprotein glomerulopathy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

While existing local therapies partially restore vision loss from diabetic retinopathy (DR), there is currently no reliable treatment to prevent the onset or stop the progression of the disease. This review seeks to explore the inflammatory molecular mechanisms underpinning DR pathogenesis, which have not been targeted by current interventions. Specifically, this review explores the role of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) protein 3 (NLRP3) inflammasome in DR onset and progression. Evidence through clinical trials has begun to note that specific drugs (fenofibrate, metformin) appear effective in slowing DR progression independent of lipid or glucose-lowering, respectively, suggesting that other mechanisms are at play. Novel therapeutics that inhibit the activation of the NLRP3 inflammasome pathway may provide a novel treatment for halting DR progression. [ABSTRACT FROM AUTHOR]

Background: Findings from cardiovascular outcome trials suggest that treatment with fenofibrate may reduce the progression of diabetic retinopathy. However, no dedicated large‐scale randomised trials have yet investigated this hypothesis. Methods: LENS is a streamlined randomised double‐masked placebo‐controlled trial, based in Scotland, assessing whether treatment with fenofibrate (145 mg tablet daily or, in the context of impaired renal function, on alternate days) in people with early retinopathy reduces progression to referable diabetic retinopathy (defined in NHS Scotland's Diabetic Eye Screening grading scheme as referable background or proliferative retinopathy, or referable maculopathy in either eye) or treatment with retinal laser, intravitreal injections or vitrectomy. Adults with diabetes mellitus and non‐referable retinopathy (mild background retinopathy in both eyes or observable background retinopathy in one/both eyes at the most recent NHS retinal screening assessment; or observable maculopathy in one/both eyes in the previous 3 years) were eligible. Potential participants were identified from routinely collected healthcare data and followed up using regular contact from the research team and linkage to national electronic morbidity, mortality, biochemistry and retinal screening records. Study treatment was mailed to participants. Results: Between 18 September 2018 and 27 July 2021, 1151 participants were randomised. Their mean age was 61 (SD 12) years, 312 (27%) were female and 305 (26%) had type 1 diabetes. 96% had bilateral mild background retinopathy and 10% had observable maculopathy. Conclusions: LENS will provide a robust evaluation of the efficacy of treating people at risk of progression of diabetic retinopathy with fenofibrate. Results are anticipated in mid‐2024. Trial Registrations: NCT03439345; ISRCTN15073006; EuDRACT 2016–002656‐24. [ABSTRACT FROM AUTHOR]

Dyslipidemia is a well-known risk factor for the development of cardiovascular diseases and atherosclerosis. The effects of combined pretreatment with atorvastatin and fenofibrate (Tricor) were studied in a mouse model of acute lipemia induced by a general lipase inhibitor, poloxamer 407 (P-407, 250 mg/kg). This lipemia is characterized by significantly increased serum levels of triglycerides (TG), low-density lipoprotein (LDL) cholesterol, together with decreased concentration of high-density lipoprotein (HDL) cholesterol. Atorvastatin pretreatment had a hypolipidemic effect, decreasing concentrations of LDL cholesterol and increasing HDL cholesterol. Pretreatment of mice with fenofibrate decreased TG level, increasing HDL cholesterol. Combined pretreatment with atorvastatin and fenofibrate decreased TG and total cholesterol. Elevation of the serum cystatin C level was found in control and lipemic mice pretreated with atorvastatin, fenofibrate, or both. Liver expression of lysosomal acid lipase increased in atorvastatin- or/and fenofibrate-pretreated groups of lipemic mice. It was concluded that increased expression of lysosomal acid lipase is related to the removal of lipid droplets from hepatocytes, thus preventing acute lipemia. Lastly, cystatin C may be a "theranostic" biomarker for hypolipidemic drugs. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a common chronic metabolic disease in humans and household cats that is characterized by persistent hyperglycemia. DM is associated with dysfunction of the intestinal barrier. This barrier is comprised of an epithelial monolayer that contains a network of tight junctions that adjoin cells and regulate paracellular movement of water and solutes. The mechanisms driving DM-associated barrier dysfunction are multifaceted, and the direct effects of hyperglycemia on the epithelium are poorly understood. Preliminary data suggest that fenofibrate, An FDA-approved peroxisome proliferator-activated receptor-alpha (PPARα) agonist drug attenuates intestinal barrier dysfunction in dogs with experimentally-induced DM. We investigated the effects of hyperglycemia-like conditions and fenofibrate treatment on epithelial barrier function using feline intestinal organoids. We hypothesized that glucose treatment directly increases barrier permeability and alters tight junction morphology, and that fenofibrate administration can ameliorate these deleterious effects. We show that hyperglycemia-like conditions directly increase intestinal epithelial permeability, which is mitigated by fenofibrate. Moreover, increased permeability is caused by disruption of tight junctions, as evident by increased junctional tortuosity. Finally, we found that increased junctional tortuosity and barrier permeability in hyperglycemic conditions were associated with increased protein kinase C-α (PKCα) activity, and that fenofibrate treatment restored PKCα activity to baseline levels. We conclude that hyperglycemia directly induces barrier dysfunction by disrupting tight junction structure, a process that is mitigated by fenofibrate. We further propose that counteracting modulation of PKCα activation by increased intracellular glucose levels and fenofibrate is a key candidate regulatory pathway of tight junction structure and epithelial permeability.

ABSTRACT 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

Abstract 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.

Abstract 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.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract 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. Graphical Abstract

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.

Abstract Background Fenofibrate is a compound with diverse biological properties that can be utilized to lower blood lipids. Understanding the impact of the gut microbiota in hyperlipidemia is vital for controlling systemic inflammation and improving serum lipid control. Nevertheless, the specific effects of fenofibrate on the phenotype and gene expression of resident gut bacteria, as well as its influence on the transformation of microbial metabolism into functional networks, remain unclear. In this study, our aimed to examine the gene and metabolic pathways of the gut microbiota in a hamster fed a high-fat diet (HFD) and administered fenofibrate. Results In this study, we conducted metagenomic analyses on samples from HFD hamsters treated with fenofibrate. The results indicated that fenofibrate treatments significantly reduce the serum lipid levels in hyperlipidemia hamsters. And the group treated with fenofibrate exhibited higher levels of beneficial bacterial species associated with health, including Bacteroides ovatus, Bifidobacterium animalis, Bacteroides intestinalis, Allobaculum stercoricanis, Lactobacillus reuteri, and Bacteroides acidifaciens, in comparison to the HFD group. Additionally, analysis of metabolic pathways demonstrated that dietary fenofibrate significantly enhanced the biosynthesis of unsaturated fatty acids, glycerophospholipid metabolism, and pyrimidine metabolism, while reducing glyoxylate and dicarboxylate metabolism, tyrosine metabolism, tryptophan metabolism, and nonribosomal peptide structures. Furthermore, these metabolic pathway changes were associated with relative alterations in the abundance of genes from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, namely K01667, K11358, K13953, K04072, K06131, K00655, K04567, K02864, K06409, K05366, K01867, K21071, and K13292. Moreover, significant changes were observed in related to carbohydrate and antibiotic resistance, such as glycosyltransferase family 51 (GT51) as well as adeC, carA, and MexT. Conclusions Dietary fenofibrate exerted significant effects on intestinal flora and genes related to lipid, energy, and amino acid metabolism, ultimately promoting a healthier colonic environment for the host. And these findings contribute to a better understanding of the mechanism of action of fenofibrate and provide a valuable foundation for future experimental and clinical studies, aiming to explore its practical applications.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]