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In a randomized trial of patients with primary biliary cholangitis, bezafibrate and ursodeoxycholic acid resulted in a higher rate of complete biochemical response than ursodeoxycholic acid alone. Bezafibrate was associated with increases in creatinine and myalgias.

The aim of this study was to assess the long-term prognosis, efficacy, and safety of combination therapy using ursodeoxycholic acid (UDCA) and bezafibrate (BF) for primary biliary cirrhosis (PBC) patients exhibiting dyslipidemia. We performed a prospective, randomized, controlled, multicenter study to compare the long-term clinical results between combination therapy and UDCA monotherapy for patients refractory to UDCA monotherapy. Twenty-seven consecutive PBC patients were enrolled. The median treatment period in the UDCA and UDCA+BF groups was 107 and 110 months, respectively. The serum alkaline phosphatase (ALP) levels and the Mayo risk score in the combination therapy group (mean 290 IU/l and 0.91, respectively) were significantly lower than those in the UDCA monotherapy group (mean 461 IU/l and 1.42, respectively) at 8 years after the beginning of the study (P<0.05). The serum creatinine levels in the combination therapy group (mean 0.94 mg/dl) were significantly higher than those in the UDCA monotherapy group (mean 0.56 mg/dl) at 8 years after the beginning of the study (P<0.05). However, the survival rate was not significantly different between the groups. We observed dose reduction or discontinuation of the administration of BF, but not UDCA, due to renal dysfunction or muscle pain. Long-term combination therapy significantly improved the serum ALP levels and the Mayo risk score. However, the survival rate was not significantly different between the groups. In addition, long-term combination therapy significantly increased the serum creatinine levels. We should pay close attention to adverse events during this long-term combination therapy.

Bezafibrate is a BCS class II drug as it presents very low solubility in water; therefore, its bioavailability after oral administration is very poor. The aim of this work was to enhance solubility and dissolution rate of bezafibrate in water in order to enhance its oral bioavailability. Several formulations were prepared using PVP K30 and Cremophor ELP employing the solvent-evaporation method and the electrospraying technique. Solubility, release rate, bioavailability in male Sprague Dawley rats, and lipid profile attributes in Wistar rats were assessed in comparison with bezafibrate plain powder. Solid-state characterization was carried out using X-ray diffraction (XRD) analysis, differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM). All the formulations exerted positive effect towards the desired goal. In particular, the optimized formulation furnished about 14-fold enhanced solubility and 85.48 ± 10.16% drug was released in 10 min as compared with bezafibrate alone (4.06 ± 2.59%). The drug existed in the amorphous state in the prepared sample as confirmed by XRD and DSC, whilst no drug-excipient interactions were observed through FTIR analysis. Moreover, SEM revealed smooth-surfaced spherical particles of the optimized formulation. A 5.5-fold higher oral bioavailability was achieved with the optimized formulation in comparison with bezafibrate plain powder. Also, TG, LDL and TC were decreased, and HDL was increased considerably in HFD-treated rats. The optimized formulation consisting of bezafibrate, PVP K30 and cremophor ELP (1/12/1.5, w/w/w) might be a capable drug delivery system for orally administering poorly water-soluble bezafibrate with improved bioavailability and antihyperlipidemic effects.

This study examined the effects of pemafibrate, a selective peroxisome proliferator-activated receptor α agonist, on the serum biochemical parameters of male patients with coronary artery disease and metabolic syndrome (MetS). This was a post hoc analysis of a randomized, crossover study that treated hypertriglyceridemia with pemafibrate or bezafibrate for 24 weeks, followed by a crossover of another 24 weeks. Of the 60 patients enrolled in the study, 55 were male. Forty-one of 55 male patients were found to have MetS. In this sub-analysis, male patients with MetS (MetS group, n  = 41) and those without MetS (non-MetS group, n  = 14) were compared. The primary endpoint was a change in fasting serum triglyceride (TG) levels during pemafibrate therapy, and the secondary endpoints were changes in insulin resistance-related markers and liver function parameters. S erum TG levels significantly decreased (MetS group, from 266.6 to 148.0 mg/dL, p  < 0.001; non-MetS group, from 203.9 to 97.6 mg/dL, p  < 0.001); however, a percent change (%Change) was not significantly different between the groups (− 44.1% vs. − 51.6%, p  = 0.084). Serum insulin levels and homeostasis model assessment of insulin resistance significantly decreased in the MetS group but not in the non-MetS group. %Change in liver enzyme levels was markedly decreased in the MetS group compared with that in the non-MetS group (alanine aminotransferase, − 25.1% vs. − 11.3%, p  = 0.027; gamma-glutamyl transferase, − 45.8% vs. − 36.2%, p  = 0.020). In conclusion, pemafibrate can effectively decrease TG levels in patients with MetS, and it may be a more efficient drug for improving insulin resistance and liver function in such patients.

This study investigates the potential interaction of the antihyperlipidemic drug Bezafibrate with Pectin for drug delivery applications, using density functional theory (DFT) calculations. A detailed analysis of the geometrical, structural, electrical, and bonding properties was conducted. This included optimized geometry, adsorption energies, quantum molecular descriptors, topological parameters, and frontier molecular orbitals. The RDG iso-surface plot of the Bezafibrate@Pectin complex revealed that strong hydrogen bonding at two distinct sites with 1.56 Å and 1.73 Å bonds length, plays a critical role in the binding process. The calculated adsorption energy (-81.62 kJ/mol) between Bezafibrate and Pectin demonstrated a favorable binding affinity, suggesting the possibility of enhanced therapeutic efficacy. Further density of state (DOS) analysis indicated that upon adsorption, Bezafibrate undergoes significant electron minor hybridization, leading to marked changes in Pectin’s electronic properties and heightened sensitivity to drug binding. The findings highlight that hydrogen bonds between the active sites of Bezafibrate and Pectin are pivotal in the adsorption mechanism of the complex. Additionally, the recovery time was estimated to analyze the interaction mechanism between the bezafibrate drug and pectin, as well as its effect on drug release. These insights contribute to the understanding of Pectin’s polysaccharides in biomedical applications, particularly for advanced drug delivery systems.

BackgroundA 14-centre study of second line therapies for PBC in England identified no difference in biochemical response rates between patients treated with Obeticholic acid (OCA) vs fibrates. However, patients treated with OCA had higher rates of ALT and bilirubin normalisation, with rates of normalisation not significant amongst fibrate treated patients. This cohort was skewed towards OCA treatment, with fibrate treated patients tending to have milder disease. We sought to examine outcomes in a clinical setting were bezafibrate (beza) was the most commonly selected second line therapy.MethodsUKPBC audit data was interrogated supplemented by case note review. Patients treated with OCA or beza for ursodeoxycholic acid (UCDA) nonresponse, with biochemistry data ≥12 months after initiation were included. Rates of discontinuation due to adverse events were noted. Third line treatments, or treatments for other indications (UCDA intolerance, itch, hyperlipidaemia) were excluded. Rates of biochemical response, ALT and bilirubin (bili) normalisation were noted. Categorical rates were compared using Chi-square and means compared using student’s t test, with a p-value of 0.05 deemed significant.Results37 patients (33 beza, 4 OCA) commenced treatment for UCDA non- response. 1 (25%) OCA patient and 5 (15%) beza patients discontinued treatment prematurely.Amongst beza treated patients 19/33 (57.6%) had an elevated ALT, and 3/33 (9%) elevated bili at baseline. Mean ALP was 388 (±146).At follow up (excluding those prematurely discontinuing treatment) 1/28 (3.6%, p < 0.001) had a raised ALT, 3/28 (10.7%, p=0.90) raised bili, and mean ALP was 149.1 (±152, p<0.001). 18/28 (64%) met Paris-1 response criteria.ConclusionsIn contrast to clinical cohorts where bezafibrate was less commonly utilised, we demonstrated ALT normalisation in all but one of 28 patients not prematurely discontinuing the drug. Bilirubin normalisation did not however occur in any of the 3 patients with elevated baseline values. High rates (64%) of Paris-1 criteria response were seen. Bezafibrate is an effective second line therapy for PBC, including those with raised ALT at baseline. Patients with raised bilirubin, who are otherwise eligible, should be considered for obeticholic acid.

Tumors undergo metabolic reprogramming to meet the energetic, synthetic and redox demands essential for malignancy, often characterized by increased glycolysis and lactate production. However, the role of mitochondrial metabolism in tumor immunity remains unclear. The present study integrates spatial transcriptomics, bulk transcriptomics and proteomics, revealing a strong link between the metabolite succinyl-CoA and tumor immunity as well as the efficacy of anti-programmed cell death protein-1 (PD-1) therapy in patients with melanoma. Elevated succinyl-CoA levels, through α-ketoglutarate or succinate supplementation, enhanced T cell-mediated tumor elimination, both in vitro and in vivo. Mechanistically, succinylation of the ligand of PD-1 (PD-L1) at lysine 129 led to its degradation. Increased carnitine palmitoyltransferase 1A (CPT1A), identified as a succinyltransferase for PD-L1, boosted anti-tumor activity. Preclinically, bezafibrate, a hyperlipidemia drug, upregulated CPT1A and synergized with CTLA-4 monoclonal antibody to inhibit tumor growth. Clinically, higher PD-L1 and lower CPT1A levels in tumors correlated with better anti-PD-1 therapy responses, suggesting potential biomarkers for prediction of treatment efficacy. Succinylation of PD-L1 by carnitine palmitoyltransferase 1A (CPT1A) in melanoma leads to its degradation and enhanced T cell-dependent killing in vitro. Increasing CPT1A levels synergizes with anti-CTLA-4 treatment to suppress tumor growth in a mouse melanoma model.

Abstract Background Bezafibrate (BZF) is effective for the treatment of hypertriglyceridemia in dogs, but there is limited data on its long-term use. Hypothesis/Objectives Assess the long-term safety and efficacy of BZF in controlling primary and secondary hypertriglyceridemia in dogs. Animals Fifty-five client-owned dogs with hypertriglyceridemia. Methods Retrospective study. Dogs were treated with BZF once daily at a median initial dosage of 5.5 mg/kg (range, 3.6-11.6 mg/kg) and classified into 3 groups: primary hypertriglyceridemia (group 1), secondary hypertriglyceridemia without changes in treatment for the underlying condition over time (group 2a) or with changes in treatment for the underlying condition over time (group 2b). Serum triglyceride (TG) concentration, and creatine kinase (CK) and alanine aminotransferase (ALT) activities were recorded before treatment (T0) and at subsequent follow-ups (1, 3, 6, 12, and >18 months, as available). Treatment response was classified as adequate (TG decreased by ≥50 % T0) or inadequate (TG decreased by <50% T0). Results All groups showed a significant decrease in TG concentration between baseline (T0) and the last available result (P <.01). No significant differences in the last follow-up TG concentration were observed among the 3 groups (P = .13). The median TG decrease across all groups during the study period was 85%. Adverse gastrointestinal or hepatic effects, possibly attributable to BZF, were observed in 4/55 dogs. Conclusions and clinical importance Long-term use of BZF proved safe and effective for most dogs with primary and secondary hypertriglyceridemia.

Background Pruritus (itch) is a frequent, burdensome and difficult-to-treat symptom in patients with cholestasis. Fibrates are currently under investigation for the treatment of primary biliary cholangitis in patients with a suboptimal response to ursodeoxycholic acid. Moreover, there is empirical evidence for a possible antipruritic effect. We aim to prove this in a randomized controlled trial, including patients with cholestatic liver diseases other than primary biliary cholangitis that are accompanied by pruritus. Methods A multicenter investigator-initiated, double-blind, randomized placebo-controlled trial to evaluate the effect of bezafibrate on cholestatic pruritus in 84 adult patients with primary biliary cholangitis or primary/secondary sclerosing cholangitis. Primary outcome is the proportion of patients with a reduction of itch intensity of 50% or more (measured on a Visual Analog Scale) after 21 days of treatment with bezafibrate 400 mg qid or placebo. Secondary outcomes include the effect of bezafibrate on a five-dimensional itch score, liver disease-specific quality of life, serum liver tests and autotaxin activity. Safety will be evaluated through serum parameters for kidney function and rhabdomyolysis as well as precise recording of (serious) adverse events. We provide a schematic overview of the study protocol and describe the methods used to recruit and randomize patients, collect and handle data and perform statistical analyses. Discussion Given its favorable safety profile and anticholestatic properties, bezafibrate may become the new first-line treatment option for treating cholestatic pruritus. Trial registration Netherlands Trial Register, ID: NCT02701166 . Registered on 2 March 2016; Netherlands Trial Register, ID: NTR5436 . Registered on 3 August 2015.

Bezafibrate (BEZ) is a drug used to treat hypertriglyceridemia and its long-term use has been associated with reduced risk of cancer in patients with coronary artery disease. Recent studies uncovered that BEZ is a potent modulator of mitochondrial biogenesis through activation of PGC-1α/PPAR complexes, resulting in modulation of lipid metabolism and fatty acid oxidation. Mitochondria impact virtually all processes linked to oncogenesis, and disruption of normal mitochondrial bioenergetics and oxidative phosphorylation (OXPHOS) occurs early during oncogenesis to change the energy metabolism of cancer cells as well as various cells in the tumor microenvironment (TME). Therefore, we synthesized a BEZ analog (Mito-BEZ) that preferentially localizes to mitochondria, thereby enabling lower doses of Mito-BEZ than BEZ to achieve greater efficacy. Our studies demonstrate that Mito-BEZ is significantly more potent than BEZ at inhibiting LUAD cell growth in vitro and inhibiting lung tumorigenesis in preclinical mouse models. Mito-BEZ was also >200-fold more potent than BEZ at inhibiting both complex I and III in LUAD cells. Furthermore, Mito-BEZ suppresses oxidative metabolism in cancer cells while markedly upregulating mitochondrial function in effector CD8+ T cells, resulting in activation of a potent T cell immune response in the TME. Our results show that Mito-BEZ, with its favorable toxicity profile, exhibited a striking inhibitory effect on lung cancer progression and metastasis by targeting a fundamental difference in metabolic plasticity between cancer cells and effector T cells in the TME.