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It is important to describe effective and non-toxic therapies for multiple sclerosis (MS), an autoimmune demyelinating disease. Experimental autoimmune encephalomyelitis (EAE) is an immune-mediated inflammatory disease that serves as a model for MS. Earlier we and others have shown that, gemfibrozil, a lipid-lowering drug, exhibits therapeutic efficacy in EAE. However, the underlying mechanism was poorly understood. Although gemfibrozil is a known ligand of peroxisome proliferator-activated receptor a (PPARa), here, we established that oral administration of gemfibrozil preserved the integrity of blood--brain barrier (BBB) and blood--spinal cord barrier (BSB), decreased the infiltration of mononuclear cells into the CNS and inhibited the disease process of EAE in both wild type and PPARα-/- mice. On the other hand, oral gemfibrozil was found ineffective in maintaining the integrity of BBB/BSB, suppressing inflammatory infiltration and reducing the disease process of EAE in mice lacking PPARb (formerly PPARd), indicating an important role of PPARβ/δ, but not PPARα, in gemfibrozil-mediated preservation of BBB/BSB and protection of EAE. Regulatory T cells (Tregs) play a critical role in the disease process of EAE/MS and we also demonstrated that oral gemfibrozil protected Tregs in WT and PPARα-/- EAE mice, but not PPARβ-/- EAE mice. Taken together, our findings suggest that gemfibrozil, a known ligand of PPARα, preserves the integrity of BBB/BSB, enriches Tregs, and inhibits the disease process of EAE via PPARβ, but not PPARα. [ABSTRACT FROM AUTHOR]

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disease affecting lipoprotein metabolism. FCS is estimated to occur in 1 in 1–2 million individuals and can be diagnosed at any age, equally affecting all genders, races, and ethnicities. The condition is characterized by hypertriglyceridemia, which may predispose patients to acute pancreatitis. In this report, we present the case of a now 6-year-old girl with FCS on gemfibrozil and dietary restrictions. The patient initially presented at 40 days of age with bloody diarrhea. Serum samples revealed lipemia, with markedly elevated triglyceride levels. The patient was diagnosed with FCS, confirmed by genetic testing showing the homozygous variant c.833C>T(p,Ser278Phe) for the LPL gene. Despite being on a low-fat diet with medium chain triglyceride (MCT) based milk formulas, the patient developed acute pancreatitis 2 months later with continued elevated triglyceride levels. She was placed on gemfibrozil and fat-soluble vitamins at 2 months of age, with marked improvements subsequently noted. Currently, the patient is doing well, with normal growth parameters and no other episodes of acute pancreatitis. Her triglyceride levels have been maintained within normal levels. FCS is a rare, inherited lipid disorder that often goes underdiagnosed and unmanaged. It is worth considering the fibric acid derivative (gemfibrozil) to be one of the lines of management early on after diagnosis.

ObjectivesTo evaluate the association between plasma metabolites, biochemical analytes, diagnostic imaging findings, and the histologic diagnosis of hepatic lipidosis in bearded dragons. To assess the effects of gemfibrozil therapy on hepatic lipid accumulation and associated diagnostic tests.AnimalsFourteen bearded dragons (Pogona vitticeps) with varying severity of hepatic lipid accumulation (with and without hepatic lipidosis) were included.ProceduresAnimals underwent coelomic ultrasound, computed tomography (CT) scans, and coelioscopic hepatic biopsies. Clinical pathology tests included lipidologic tests, hepatic biomarkers, and mass spectrometry-based metabolomics. Animals were medicated with gemfibrozil 6mg/kg orally once a day for 2 months in a randomized blinded clinical trial prior to repeating previous diagnostic testing.ResultsHounsfield units on CT were negatively associated with increased hepatic vacuolation, while ultrasound and gross evaluation of the liver were not reliable. Beta-hydroxybutyric-acid (BHBA) concentrations were significantly associated with hepatic lipidosis. Metabolomics and lipidomics data found BHBA and succinic acid to be potential biomarkers for diagnosing hepatic lipidosis in bearded dragons. Succinic acid concentrations were significantly lower in the gemfibrozil treatment group. There was a tendency for improvement in the biomarkers and reduced hepatic fat in bearded dragons with hepatic lipidosis when treated with gemfibrozil, though the improvement was not statistically significant.ConclusionsThese findings provide information on the antemortem assessment of hepatic lipidosis in bearded dragons and paves the way for further research in diagnosis and treatment of this disease.

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disease affecting lipoprotein metabolism. FCS is estimated to occur in 1 in 1–2 million individuals and can be diagnosed at any age, equally affecting all genders, races, and ethnicities. The condition is characterized by hypertriglyceridemia, which may predispose patients to acute pancreatitis. In this report, we present the case of a now 6-year-old girl with FCS on gemfibrozil and dietary restrictions. The patient initially presented at 40 days of age with vomiting. Serum samples revealed lipemia, with markedly elevated triglyceride levels. The patient was diagnosed with FCS, confirmed by genetic testing showing the homozygous variant c.833C>T(p,Ser278Phe) for the LPL gene. Despite being on a low-fat diet with medium chain triglyceride (MCT) based milk formulas, the patient developed acute pancreatitis 2 months later with continued elevated triglyceride levels. She was placed on gemfibrozil and fat-soluble vitamins at 2 months of age, with marked improvements subsequently noted. Currently, the patient is doing well, with normal growth parameters and no other episodes of acute pancreatitis. Her triglyceride levels have been maintained within normal levels. FCS is a rare, inherited lipid disorder that often goes underdiagnosed and unmanaged. It is worth considering the fibric acid derivative (gemfibrozil) to be one of the lines of management early on after diagnosis. [ABSTRACT FROM AUTHOR]

Neuronal ceroid-lipofuscinosis (NCLs) are a group of severe neurodegenerative conditions, most likely present in infantile, late infantile, juvenile, and adult-onset forms. Their phenotypic characteristics comprise eyesight damage, reduced motor activity and cognitive function, and sometimes tend to die in the initial stage. In recent studies, NCLs have been categorized into at least 14 genetic collections (CLN1-14). CLN2 gene encodes Tripeptidyl peptidase 1 (TPP1), which affects late infantile-onset form. In this study, we retrieved a mutational dataset screening for TPP1 protein from various databases (ClinVar, UniProt, HGMD). Fifty-six missense mutants were enumerated with computational methods to perceive the significant mutants (G475R and G501C) and correlated with clinical and literature data. A structure-based screening method was initiated to understand protein-ligand interaction and dynamic simulation. The docking procedure was performed for the native (3EDY) and mutant (G473R and G501C) structures with Gemfibrozil (gem), which lowers the lipid level, decreases the triglycerides amount in the blood circulation, and controls hyperlipidemia. The Native had an interaction score of -5.57 kcal/mol, and the mutants had respective average binding scores of -6.24 (G473R) and − 5.17 (G501C) kcal/mol. Finally, molecular dynamics simulation showed that G473R and G501C mutants had better flexible and stable orientation in all trajectory analyses. Therefore, this work gives an extended understanding of both functional and structural levels of influence for the mutant form that leads to NCL disorder. [ABSTRACT FROM AUTHOR]

Background: Gemfibrozil (Gem) is a drug that has been shown to activate PPAR‐α, a nuclear receptor that plays a key role in regulating lipid metabolism. Gem is used to lower the levels of triglycerides and reduce the risk of coronary heart disease in patients. Experimental studies in vitro and in vivo have shown that Gem can prevent or slow the progression of neurological disorders (NDs), including cerebral ischemia (CI), Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Neuroinflammation is known to play a significant role in these disorders. Method: The literature review for this study was conducted by searching Scopus, Science Direct, PubMed, and Google Scholar databases. Result: The results of this study show that Gem has neuroprotective effects through several cellular and molecular mechanisms such as: (1) Gem has the ability to upregulate pro‐survival factors (PGC‐1α and TFAM), promoting the survival and function of mitochondria in the brain, (2) Gem strongly inhibits the activation of NF‐κB, AP‐1, and C/EBPβ in cytokine‐stimulated astroglial cells, which are known to increase the expression of iNOS and the production of NO in response to proinflammatory cytokines, (3) Gem protects dopamine neurons in the MPTP mouse model of PD by increasing the expression of PPARα, which in turn stimulates the production of GDNF in astrocytes, (4) Gem reduces amyloid plaque pathology, reduces the activity of glial cells, and improves memory, (5) Gem increases myelin genes expression (MBP and CNPase) via PPAR‐β, and (6) Gem increases hippocampal BDNF to counteract depression. Conclusion: According to the study, Gem was investigated for its potential therapeutic effect in NDs. Further research is needed to fully understand the therapeutic potential of Gem in NDs. [ABSTRACT FROM AUTHOR]

This article presents a comparative study on the benefits of different treatments for rats with streptozotocin-induced diabetes. The study found that a combination therapy of insulin, rosiglitazone, and gemfibrozil was more effective in controlling blood sugar and lipid levels compared to individual treatments. The combination therapy also had a positive effect on lipid levels, reducing cholesterol and triglycerides while increasing HDL. The study suggests that this combination therapy may help prevent cardiovascular events associated with diabetes. [Extracted from the article]

Introduction: Increased blood lipids are an important factor in the occurrence of cardiovascular diseases and heart attacks in humans. The aim of this study is to compare the effect of the traditional medicine product Lipexan with placebo along with Gemfibrozil on blood lipid indicators. Material and methods: This study was conducted as a double-blind randomized clinical trial with a parallel design, on 109 patients with hyperlipidemia. After entering the study, patients were randomly divided into two groups receiving Lipexan herbal capsules (containing garlic, sumac, apple cider vinegar, fenugreek and dill) and placebo capsules. Both groups received Gemfibrozil capsules at the same time and were prescribed the same diet. The duration of treatment was 40 days. The lipid profile of the patients was checked before and after taking the drugs. Results: In the Lipexan drug treatment group, the average blood triglyceride before taking the drug was 362.2 mg/dl, which reached 243.1 mg/dl after taking the drug. Also, the average blood cholesterol before and after taking the drug was 201.4 and 187.7, respectively. Statistically, there was a significant decrease in triglyceride, total cholesterol, Low Density Lipoprotein, High Density Lipoprotein, fasting blood sugar and alkaline Phosphatase after taking Lipexan drug (P<0.05). Conclusion: The present study shows that Lipexan herbal capsule is effective in reducing blood fats and lipid profile in hyperlipidemia patients compared to placebo capsule. [ABSTRACT FROM AUTHOR]

Diabetes-associated cognitive dysfunction (DACD) is considered a significant complication of diabetes and manifests as cognitive impairment. Astrocytes are vital to the brain energy metabolism and cerebral antioxidant status. Ferroptosis has been implicated in cognitive impairment, but it is unclear whether the ferroptosis of astrocytes is involved in the progression of DACD. PPARA/PPARα (peroxisome proliferator-activated receptor alpha) is a transcription factor that regulates glucose and lipid metabolism in the brain. In this study, we demonstrated that high glucose promoted ferroptosis of astrocytes by disrupting iron metabolism and suppressing the xCT/GPX4-regulated pathway in diabetic mice and astrocytes cultured in high glucose. Administration of gemfibrozil, a known PPARα agonist, inhibited ferroptosis and improved memory impairment in db/db mice. Gemfibrozil also prevented the accumulation of lipid peroxidation products and lethal reactive oxygen species induced by iron deposition in astrocytes and substantially reduced neuronal and synaptic loss. Our findings demonstrated that ferroptosis of astrocytes is a novel mechanism in the development of DACD. Additionally, our study revealed the therapeutic effect of gemfibrozil in preventing and treating DACD by inhibiting ferroptosis. [ABSTRACT FROM AUTHOR]

Recent studies observed, despite an anti-hyperlipidaemic effect, a positive impact of fibrates on septic conditions. This study evaluates the effects of gemfibrozil on microcirculatory variables, mitochondrial function, and lipid peroxidation levels with regard to its potential role as an indicator for oxidative stress in the colon and liver under control and septic conditions and dependencies on PPARα-mediated mechanisms of action. With the approval of the local ethics committee, 120 Wistar rats were randomly divided into 12 groups. Sham and septic animals were treated with a vehicle, gemfibrozil (30 and 100 mg/kg BW), GW 6471 (1 mg/kg BW, PPARα inhibitor), or a combination of both drugs. Sepsis was induced via the colon ascendens stent peritonitis (CASP) model. Then, 24 h post sham or CASP surgery, a re-laparotomy was performed. Measures of vital parameters (heart rate (HR), mean arterial pressure (MAP), and microcirculation (µHbO2)) were recorded for 90 min. Mitochondrial respirometry and assessment of lipid peroxidation via a malondialdehyde (MDA) assay were performed on colon and liver tissues. In the untreated sham animals, microcirculation remained stable, while pre-treatment with gemfibrozil showed significant decreases in the microcirculatory oxygenation of the colon. In the CASP animals, µHbO2 levels in the colon and the liver were significantly decreased 90 min after laparotomy. Pre-treatment with gemfibrozil prevented the microcirculatory aberrations in both organs. Gemfibrozil did not affect mitochondrial function and lipid peroxidation levels in the sham or CASP animals. Gemfibrozil treatment influences microcirculation depending on the underlying condition. Gemfibrozil prevents sepsis-induced microcirculatory aberrances in the colon and liver PPARα-independently. In non-septic animals, gemfibrozil impairs the microcirculatory variables in the colon without affecting those in the liver. [ABSTRACT FROM AUTHOR]

Tay-Sachs disease (TSD) is a progressive heritable neurodegenerative disorder characterized by the deficiency of the lysosomal β-hexosaminidase enzyme (Hex−/−) and the storage of GM2 ganglioside, as well as other related glycoconjugates. Along with motor difficulties, TSD patients also manifest a gradual loss of skills and behavioral problems, followed by early death. Unfortunately, there is no cure for TSD; however, research on treatments and therapeutic approaches is ongoing. This study underlines the importance of gemfibrozil (GFB), an FDA-approved lipid-lowering drug, in inhibiting the disease process in a transgenic mouse model of Tay-Sachs. Oral administration of GFB significantly suppressed glial activation and inflammation, while also reducing the accumulation of GM2 gangliosides/glycoconjugates in the motor cortex of Tay-Sachs mice. Furthermore, oral GFB improved behavioral performance and increased the life expectancy of Tay-Sachs mice. While investigating the mechanism, we found that oral administration of GFB increased the level of peroxisome proliferator-activated receptor α (PPARα) in the brain of Tay-Sachs mice, and that GFB remained unable to reduce glycoconjugates and improve behavior and survival in Tay-Sachs mice lacking PPARα. Our results indicate a beneficial function of GFB that employs a PPARα-dependent mechanism to halt the progression of TSD and increase longevity in Tay-Sachs mice. [ABSTRACT FROM AUTHOR]

It is important to describe effective and non-toxic therapies for multiple sclerosis (MS), an autoimmune demyelinating disease. Experimental autoimmune encephalomyelitis (EAE) is an immune-mediated inflammatory disease that serves as a model for MS. Earlier we and others have shown that, gemfibrozil, a lipid-lowering drug, exhibits therapeutic efficacy in EAE. However, the underlying mechanism was poorly understood. Although gemfibrozil is a known ligand of peroxisome proliferator-activated receptor α (PPARα), here, we established that oral administration of gemfibrozil preserved the integrity of blood–brain barrier (BBB) and blood–spinal cord barrier (BSB), decreased the infiltration of mononuclear cells into the CNS and inhibited the disease process of EAE in both wild type and PPARα–/– mice. On the other hand, oral gemfibrozil was found ineffective in maintaining the integrity of BBB/BSB, suppressing inflammatory infiltration and reducing the disease process of EAE in mice lacking PPARβ (formerly PPARδ), indicating an important role of PPARβ/δ, but not PPARα, in gemfibrozil-mediated preservation of BBB/BSB and protection of EAE. Regulatory T cells (Tregs) play a critical role in the disease process of EAE/MS and we also demonstrated that oral gemfibrozil protected Tregs in WT and PPARα–/– EAE mice, but not PPARβ–/– EAE mice. Taken together, our findings suggest that gemfibrozil, a known ligand of PPARα, preserves the integrity of BBB/BSB, enriches Tregs, and inhibits the disease process of EAE via PPARβ, but not PPARα.

In the presented method, modified magnetic nickel oxide was synthesized and identified for pre-concentration and determination of gemfibrozil in human serum samples, pharmaceutical wastewater and drug. Fourier transform infrared spectrum (FTIR), X-ray diffraction (XRD) and scanning electron microscope (SEM) were used to identify magnetic nickel oxide nanoparticles. Some parameters affecting the extraction, including pH effect, amount and type of elution solvent, extraction time, etc., were optimized and investigated. The concentration factor was 120, the limit of detection (LOD) was 0.16 µg.L-1, and the linear range of the calibration curve was 0.05 to 10 µg.L-1. The adsorption capacity was 52.69 mg.g-1. This method was successfully used to determination of gemfibrozile in human serum samples, pharmaceutical wastewater and drug using UV-Vis spectrometer with recovery in the range of 0.98-0.104%. Then, the samples determined by the proposed method with the results of the standard high-performance liquid chromatography (HPLC) method were compared. The results were checked with T-test and showed that there is no significant difference between the two methods.

Kidney dysfunction significantly increases the cardiovascular risk, even in cases of minor functional declines. Hypertriglyceridemia is the most common lipid abnormality reported in patients with kidney disorders. PPAR-α (peroxisome proliferator-activated receptor-α) agonists called fibrates are the main agents used to lower triglyceride levels. Kynurenic acid (KYNA) is a tryptophan (Trp) derivative directly formed from L-kynurenine (L-KYN) by kynurenine aminotransferases (KATs). KYNA is classified as a uremic toxin, the level of which is correlated with kidney function impairments and lipid abnormalities. The aim of this study was to analyze the effect of the most commonly used triglyceride-lowering drugs, fenofibrate and gemfibrozil, on KYNA production and KAT activity in rat kidneys in vitro. The influence of fenofibrate and gemfibrozil on KYNA formation and KAT activity was tested in rat kidney homogenates in vitro. Fenofibrate and gemfibrozil at 100 µM–1 mM significantly inhibited KYNA synthesis in rat kidney homogenates. Both fibrates directly affected the KAT I and KAT II isoenzyme activities in a dose-dependent manner at similar concentrations. The presented results reveal the novel mechanism of action of fibrates in the kidneys and suggest their potential role in kidney function protection beyond the well-known anti-hyperlipidemic effect. [ABSTRACT FROM AUTHOR]

Copyright of Actualités Pharmaceutiques is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Gemfibrozil (GFZ) is a medication of the fibrate category with agonistic effects on peroxisome proliferator‐activated receptor‐α (PPAR‐α) and is effective for hypertriglyceridemia and mixed dyslipidemia. This agent also has anti‐inflammatory and antioxidant properties. The current study investigated the effects of GFZ on hepatorenal damages in a D‐galactose (D‐gal)‐induced aging model. We used 28 male mice, which were equally and randomly divided into four groups as follows: normal, D‐gal (150 mg/kg/day; intraperitoneal [i.p.], for 6 weeks), GFZ (100 mg/kg/day GFZ, orally [p.o.] for 6 weeks), and the combined D‐gal + GFZ. Liver and kidney function indices were measured as serum creatinine, blood urine nitrogen, alanine aminotransferase, and aspartate aminotransferase. Oxidative stress in hepatic and renal tissue was evaluated through malondialdehyde, superoxide dismutase, and glutathione peroxidase levels. Finally, the liver and kidney tissues were assessed for histopathological lesions. The results showed that D‐gal‐induced aging leads to abnormalities in liver and kidney function indices. D‐gal also induced significant oxidative stress and histopathological lesions in these organs. GFZ improved function indices and oxidative stress compared to the D‐gal‐treated animals. Histological evaluations of the liver and kidney also confirmed these results. These data provide evidence for the potential therapeutic of GFZ in clinical practice for mitigating the hepatorenal damages of aging. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Agro-Environment Science is the property of Journal of Agro-Environment Science Editorial Board and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Juvenile neuronal ceroid lipofuscinosis (JNCL) is a fatal inherited neurodegenerative disease of children that occurs because of defective function of the lysosomal membrane glycoprotein CLN3. JNCL features glial activation and accumulation of autofluorescent storage material containing subunit c of mitochondrial ATP synthase (SCMAS), ultimately resulting into neuronal loss. Until now, no effective therapy is available for JNCL. This study underlines the possible therapeutic importance of gemfibrozil, an activator of peroxisome proliferator-activated receptor a (PPARa) and a lipid-lowering drug approved by the Food and Drug Administration in an animal model of JNCL. Oral gemfibrozil treatment reduced microglial and astroglial activation, attenuated neuroinflammation, restored the level of transcription factor EB (TFEB; the master regulator of lysosomal biogenesis), and decreased the accumulation of storage material SCMAS in somatosensory barrel field (SBF) cortex of Cln3Dex7/8 (Cln3DJNCL) mice of both sexes. Accordingly, gemfibrozil treatment also improved locomotor activities of Cln3DJNCL mice. While investigating the mechanism, we found marked loss of PPARa in the SBF cortex of Cln3DJNCL mice, which increased after gemfibrozil treatment. Oral gemfibrozil also stimulated the recruitment of PPARa to the Tfeb gene promoter in vivo in the SBF cortex of Cln3DJNCL mice, indicating increased transcription of Tfeb in the CNS by gemfibrozil treatment via PPARa. Moreover, disease pathologies aggravated in Cln3DJNCL mice lacking PPARa (Cln3DJNCLDPPARa) and gemfibrozil remained unable to decrease SCMAS accumulation, reduce glial activation, and improve locomotor performance of Cln3DJNCLDPPARa mice. These results suggest that activation of PPARa may be beneficial for JNCL and that gemfibrozil may be repurposed for the treatment of this incurable disease. [ABSTRACT FROM AUTHOR]

All regulatory organizations are paying close attention to the identification and measurement of genotoxic contaminants. Using conventional analytical techniques like high-performance liquid chromatography (HPLC) and gas chromatography to quantify probable genotoxic substances (PGIs) at the trace level is difficult (GC). Therefore, there is a necessity for advanced analytical techniques for the development of highly sensitive analytical procedures for the determination of trace-level PGIs in drug products and drug substances. This study's goal is to develop and evaluate an analytical technique for measuring allyl chloride, a possible genotoxic contaminant in gemfibrozil. For the detection of very low and trace levels of impurities, a gas chromatography with a triple quadrupole mass spectrometry detector (GC-MS/MS) approach was developed and validated. Using a column USP phase G27, a nonpolar and low bleed 5% diphenyl, 95% dimethylpolysiloxane, with dimensions of 30 m in length, 0.32 mm internal diameters, and 1.5 m film thickness, along with a flow rate of 2.0 mL/min and Helium (He) as a carrier gas, this method uses a thermal gradient elution program. The method was calibrated with a linearity range from 30% to 150% concentration with respect to the specification level and achieved a limit of detection (LOD) and limit of quantification (LOQ) were 0.005 ppm and 0.01 ppm, respectively, for allyl chloride. According to current ICH requirements, the method was validated, and it was discovered to be specific, exact, accurate, linear, sensitive, tough, robust, and stable. This method is suitable for determining allyl chloride in the regular analysis of Gemfibrozil. [ABSTRACT FROM AUTHOR]

Simple Summary: Pharmaceuticals used to treat abnormal cholesterol levels in the blood are known as lipid regulators (fibrates and statins), and their use is in constant growth. Treatment plants are usually unable to efficiently remove these compounds from wastewater, where their degradation rate is considerably slow, making them an emerging concern for aquatic systems. The present work reviews previously published research concerning the effects of these pharmaceuticals on several finfish species worldwide. Results suggest that both short- and long-term exposure to lipid regulators may have negative effects on fish health, affecting their metabolism and immune system and causing reproductive and developmental disorders. However, the information on these compounds in the available literature is still limited, and additional research is needed to fully understand the threat that their presence in aquatic systems may pose to the production of finfish by the aquaculture industry. The most documented fibrates are gemfibrozil, clofibrate and bezafibrate, while for statins, the majority of the published literature focuses on atorvastatin and simvastatin. The present work reviews previously published research concerning the effects of these hypocholesterolaemic pharmaceuticals on fish, with a particular focus on commercially important species, commonly produced by the European aquaculture industry, specifically in recirculated aquaculture systems (RAS). Overall, results suggest that both acute and chronic exposures to lipid-lowering compounds may have adverse effects on fish, disrupting their capacity to excrete exogenous substances, as well as both lipid metabolism and homeostasis, causing severe ontogenetic and endocrinological abnormalities, leading to hampered reproductive success (e.g., gametogenesis, fecundity), and skeletal or muscular malformations, having serious repercussions on fish health and welfare. Nonetheless, the available literature focusing on the effects of statins or fibrates on commonly farmed fish is still limited, and further research is required to understand the implications of this matter on aquaculture production, global food security and, ultimately, human health. [ABSTRACT FROM AUTHOR]

Tay-Sachs disease (TSD) is a progressive heritable neurodegenerative disorder characterized by the deficiency of the lysosomal β-hexosaminidase enzyme (Hex−/−) and the storage of GM2 ganglioside, as well as other related glycoconjugates. Along with motor difficulties, TSD patients also manifest a gradual loss of skills and behavioral problems, followed by early death. Unfortunately, there is no cure for TSD; however, research on treatments and therapeutic approaches is ongoing. This study underlines the importance of gemfibrozil (GFB), an FDA-approved lipid-lowering drug, in inhibiting the disease process in a transgenic mouse model of Tay-Sachs. Oral administration of GFB significantly suppressed glial activation and inflammation, while also reducing the accumulation of GM2 gangliosides/glycoconjugates in the motor cortex of Tay-Sachs mice. Furthermore, oral GFB improved behavioral performance and increased the life expectancy of Tay-Sachs mice. While investigating the mechanism, we found that oral administration of GFB increased the level of peroxisome proliferator-activated receptor α (PPARα) in the brain of Tay-Sachs mice, and that GFB remained unable to reduce glycoconjugates and improve behavior and survival in Tay-Sachs mice lacking PPARα. Our results indicate a beneficial function of GFB that employs a PPARα-dependent mechanism to halt the progression of TSD and increase longevity in Tay-Sachs mice.

Gemfibrozil is a drug that has been used for over 40 years to lower triglycerides in blood. As a ligand for peroxisome proliferative-activated receptor-alpha (PPARα), which is expressed in many tissues, it induces the transcription of numerous genes for carbohydrate and lipid-metabolism. However, nothing is known about how intracellular lipid-homeostasis and, in particular, triglycerides are affected. As triglycerides are stored in lipid-droplets, which are known to be associated with many diseases, such as Alzheimer's disease, cancer, fatty liver disease and type-2 diabetes, treatment with gemfibrozil could adversely affect these diseases. To address the question whether gemfibrozil also affects intracellular lipid-levels, SH-SY5Y, HEK and Calu-3 cells, representing three different metabolically active organs (brain, lung and kidney), were incubated with gemfibrozil and subsequently analyzed semi-quantitatively by mass-spectrometry. Importantly, all cells showed a strong increase in intracellular triglycerides (SH-SY5Y: 170.3%; HEK: 272.1%; Calu-3: 448.1%), suggesting that the decreased triglyceride-levels might be due to an enhanced cellular uptake. Besides the common intracellular triglyceride increase, a cell-line specific alteration in acylcarnitines are found, suggesting that especially in neuronal cell lines gemfibrozil increases the transport of fatty acids to mitochondria and therefore increases the turnover of fatty acids for the benefit of additional energy supply, which could be important in diseases, such as Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Herein, polydopamine‐coated Fe3O4 spheres were synthesized using a very simple, easy, cost‐effective, efficient, and fast method. First, magnetic nanoparticles (Fe3O4) were synthesized and were followed by accommodating polydopamine on the surface of the prepared Fe3O4. The prepared polydopamine‐coated Fe3O4 spheres were utilized as a sorbent in magnetic solid phase extraction of gemfibrozil and warfarin (as the model analytes). The extracted model analytes were desorbed by a suitable organic solvent and were analyzed by high‐performance liquid chromatography. Under optimized condition, the linearity of the method was in the range of 0.1–200.0 μg/L for the selected analytes in water. The limits of detection were calculated to be in the range of 0.026–0.055 μg/L for warfarin and gemfibrozil, respectively. The limits of quantification were calculated to be in the range of 0.089–0.185 μg/L. The inter‐day and intra‐day relative standard deviations were determined to be in the range of 1.4%–3.3% in three concentrations in order to calculate the method precision. Furthermore, the enrichment factors were found to be 78 and 81 for warfarin and gemfibrozil, respectively. Moreover, the calculated absolute recoveries were between 78% and 81%. The obtained recoveries indicated that the method was useful and applicable in complicated real samples. [ABSTRACT FROM AUTHOR]

Introduction: Drug-induced pancreatitis has been increasingly recognized, but it is frequently encountered as an inconspicuous etiology. The underlying mechanisms of injury vary with different drugs. Tamoxifen is a frequently used anticancer drug that acts by selective modulation of the estrogen receptor in patients with breast cancer. Tamoxifen-induced hypertriglyceridemia is a relatively rare etiological factor for acute pancreatitis. However, acute pancreatitis secondary to this adverse effect remains an exceedingly important clinicopathologic entity. Case report: We hereby delineate a rare case of acute pancreatitis secondary to hypertriglyceridemia in a patient who was on tamoxifen treatment for the past 3 years. Her serum lipase and triglyceride levels were markedly elevated at 14,285 IU/L and 20,344 mg/dL, respectively. The diagnosis was considered based on the findings of a standard diagnostic workup and exclusion of alternative causes of acute pancreatitis. Management and outcome: The patient was instituted prompt treatment with intravenous insulin infusion and gemfibrozil. The clinical outcome was favorable with no complications. Tamoxifen was permanently discontinued and was replaced with letrozole. Discussion: This article illustrates that acute pancreatitis should be considered in the differential diagnoses of abdominal pain and elevated pancreatic enzymes in patients undergoing tamoxifen treatment. It also underscores the importance of pre- and post-tamoxifen lipid screening, especially in patients with a history of dyslipidemia and diabetes mellitus. It will facilitate an expedient detection of hypertriglyceridemia, potentially saving patients from associated morbidity and mortality. [ABSTRACT FROM AUTHOR]

UDP‐glucuronosyltransferases (UGTs) catalyze the conjugation of various substrates with sugars. Since the UGT2 family forms a large cluster spanning 1.5 Mb, transgenic mouse lines carrying the entire human UGT2 family have not been constructed because of limitations in conventional cloning techniques. Therefore, we made a humanized mouse model for UGT2 by chromosome engineering technologies. The results showed that six UGT2 isoforms examined were expressed in the liver of adult humanized UGT2 (hUGT2) mice. Thus, the functions of human UGT2B7 in the liver of hUGT2 mice were evaluated. Glucuronide of azidothymidine (AZT, zidovudine), a typical UGT2B7 substrate, was formed in the liver microsomes of hUGT2 mice but not in the liver microsomes of wild‐type and Ugt2‐knockout mice. When AZT was intravenously administered, AZT glucuronide was detected in the bile and urine of hUGT2 mice, but it was not detected in the bile and urine of wild‐type and Ugt2‐knockout mice. These results indicated that the hUGT2 mice express functional human UGT2B7 in the liver. This finding was also confirmed by using gemfibrozil as an alternative UGT2B7 substrate. Gemfibrozil glucuronide was formed in the liver microsomes of hUGT2 mice and was mainly excreted in the bile of hUGT2 mice after intravenous dosing of gemfibrozil. This hUGT2 mouse model will enable improved predictions of pharmacokinetics, urinary and biliary excretion and drug–drug interactions mediated by human UGT2, at least UGT2B7, in drug development research and basic research. [ABSTRACT FROM AUTHOR]

Pharmaceutical pollution of water bodies is among the top-notch environmental health risks all over the world. The aim of the present study was to investigate the effects of two common pharmaceuticals namely ibuprofen and gemfibrozil on zebrafish at environmentally relevant concentrations. In zebrafish liver, gemfibrozil caused a decrease in glutathione and glutathione transferase and an increase in catalase but had no effect on lipid peroxidation and protein carbonylation. Ibuprofen altered the antioxidant defense system, promoted protein carbonylation in zebrafish liver, and increased vitellogenin-like protein in the blood. Ibuprofen and particularly gemfibrozil induced lysosomes biogenesis. Lactate dehydrogenase in the blood was also found to be higher in the studied groups. Studied pharmaceuticals did not affect complex II of the electron respiratory chain. Ibuprofen affects zebrafish health status more profoundly than gemfibrozil. Our results showed that pharmaceuticals even in low, environmentally realistic concentrations, induced profound changes in the stress-responsive systems of zebrafish. [ABSTRACT FROM AUTHOR]

Kidney dysfunction significantly increases the cardiovascular risk, even in cases of minor functional declines. Hypertriglyceridemia is the most common lipid abnormality reported in patients with kidney disorders. PPAR-α (peroxisome proliferator-activated receptor-α) agonists called fibrates are the main agents used to lower triglyceride levels. Kynurenic acid (KYNA) is a tryptophan (Trp) derivative directly formed from L-kynurenine (L-KYN) by kynurenine aminotransferases (KATs). KYNA is classified as a uremic toxin, the level of which is correlated with kidney function impairments and lipid abnormalities. The aim of this study was to analyze the effect of the most commonly used triglyceride-lowering drugs, fenofibrate and gemfibrozil, on KYNA production and KAT activity in rat kidneys in vitro. The influence of fenofibrate and gemfibrozil on KYNA formation and KAT activity was tested in rat kidney homogenates in vitro. Fenofibrate and gemfibrozil at 100 µM–1 mM significantly inhibited KYNA synthesis in rat kidney homogenates. Both fibrates directly affected the KAT I and KAT II isoenzyme activities in a dose-dependent manner at similar concentrations. The presented results reveal the novel mechanism of action of fibrates in the kidneys and suggest their potential role in kidney function protection beyond the well-known anti-hyperlipidemic effect.

The present study was designed to assess the treatment effect of arginase inhibitor, L-Norvaline in abnormalities associated with high fat diet (HFD) and fructose-induced metabolic syndrome. The HFD and fructose was fed to the rats for a period of 45 days. Animals having body weight of 350 g and fasting blood sugar level of more than 250 mg/dl were considered as hyperlipidemic diabetic rats (HDR) and selected for the study. The HDR were divided into three groups having six animals each. The HDR received L–Norvaline (10 mg/kg/day, i.p.) and standard drug, gemfibrozil (60 mg/kg/day, p.o.), for a period of 30 days. Various hormonal, biochemical and tissue parameters were evaluated at the end of the study. Both treatments significantly decreased body weight, BMI, fasting blood sugar and insulin level and improved insulin resistance in HDR as compared to the toxicant control group. A significant improvement was observed in the lipid profile, levels of nitrate, leptin, C-reactive protein and adiponectin in HDR. L-Norvaline also caused slight decrease in the malondialdehyde level, though, no prominent effect was observed on the level of superoxide dismutase and reduced glutathione in the pancreas of HDR, as compared to the toxicant control group. L-Norvaline treatment also improved the histo-architecture of pancreatic cells. Results of the present study concludes that L-Norvaline caused significant alleviation of the abnormalities of MetS indicating that it can be used as potential treatment strategy for managing the symptoms of metabolic syndrome.

Abstract UDP‐glucuronosyltransferases (UGTs) catalyze the conjugation of various substrates with sugars. Since the UGT2 family forms a large cluster spanning 1.5 Mb, transgenic mouse lines carrying the entire human UGT2 family have not been constructed because of limitations in conventional cloning techniques. Therefore, we made a humanized mouse model for UGT2 by chromosome engineering technologies. The results showed that six UGT2 isoforms examined were expressed in the liver of adult humanized UGT2 (hUGT2) mice. Thus, the functions of human UGT2B7 in the liver of hUGT2 mice were evaluated. Glucuronide of azidothymidine (AZT, zidovudine), a typical UGT2B7 substrate, was formed in the liver microsomes of hUGT2 mice but not in the liver microsomes of wild‐type and Ugt2‐knockout mice. When AZT was intravenously administered, AZT glucuronide was detected in the bile and urine of hUGT2 mice, but it was not detected in the bile and urine of wild‐type and Ugt2‐knockout mice. These results indicated that the hUGT2 mice express functional human UGT2B7 in the liver. This finding was also confirmed by using gemfibrozil as an alternative UGT2B7 substrate. Gemfibrozil glucuronide was formed in the liver microsomes of hUGT2 mice and was mainly excreted in the bile of hUGT2 mice after intravenous dosing of gemfibrozil. This hUGT2 mouse model will enable improved predictions of pharmacokinetics, urinary and biliary excretion and drug–drug interactions mediated by human UGT2, at least UGT2B7, in drug development research and basic research.

Background and Objective: Tucatinib is approved for treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer. Understanding potential drug-drug interactions (DDIs) informs proper dosing when co-administering tucatinib with other therapies. The aim of this study was to evaluate DDIs between tucatinib and metabolizing enzymes and transporters in healthy volunteers.Methods: Parts A-C assessed the impact of itraconazole (cytochrome P450 [CYP] 3A4 inhibitor), rifampin (CYP3A4/CYP2C8 inducer), or gemfibrozil (CYP2C8 inhibitor) on the pharmacokinetics of a single 300 mg dose of tucatinib administered orally and its primary metabolite, ONT-993. Parts D and E assessed the effect of steady-state tucatinib on the pharmacokinetics of repaglinide (CYP2C8 substrate), tolbutamide (CYP2C9 substrate), midazolam (CYP3A4 substrate), and digoxin (P-glycoprotein substrate).Results: Tucatinib area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-inf) increased by ~ 1.3- and 3.0-fold with itraconazole and gemfibrozil, respectively, and decreased by 48% with rifampin, indicating that tucatinib is metabolized primarily by CYP2C8, and to a lesser extent via CYP3A. Tucatinib was a strong inhibitor of CYP3A (midazolam AUC0-inf increased 5.7-fold), a weak inhibitor of CYP2C8 and P-glycoprotein, and had no impact on CYP2C9-mediated metabolism in humans. Tucatinib was well tolerated, alone and with co-administered drugs.Conclusion: The potential DDIs identified here may be mitigated by avoiding concomitant use of tucatinib with strong CYP3A inducers, moderate CYP2C8 inducers, CYP3A substrates with a narrow therapeutic window (modifying substrate dose where concomitant use is unavoidable), and strong CYP2C8 inhibitors (decreasing tucatinib dose where concomitant use is unavoidable), or by reducing the dose of P-glycoprotein substrates with a narrow therapeutic window.Trial Registration: This trial (NCT03723395) was registered on October 29, 2018. [ABSTRACT FROM AUTHOR]

The lipid-regulating drug gemfibrozil is a useful medication for reducing high cholesterol and triglycerides in the blood. In addition to oxidation, it undergoes extensive glucuronidation to produce gemfibrozil acyl glucuronide, which is a known mechanism-based inactivator of cytochrome P450 (CYP) 2C8. Such selective and time-dependent inhibition results in clinically important drug–drug interactions (DDI) with the drugs metabolized by CYP2C8. Similarly, the acyl glucuronide of clopidogrel, a widely used antiplatelet agent, is a potent time-dependent inhibitor of CYP2C8 that demonstrated significant DDI with the substrates of CYP2C8. Current progress in atomic-level understanding mostly involves studying how different drugs bind and undergo oxidation in the active site of CYPs. It is not clear how an acyl glucuronide metabolite of the drug gemfibrozil or clopidogrel interacts in the active site of CYP2C8 and selectively inhibit the enzyme. This mini-review summarizes the current knowledge on some of the important clinical DDI caused by gemfibrozil and clopidogrel due to the inhibition of CYP2C8 by acyl glucuronide metabolites of these drugs. Importantly, it examines recent developments and potential applications of structural biology tools to elucidate the binding and orientation of gemfibrozil acyl glucuronide and clopidogrel acyl glucuronide in the active site near heme that contributes to the inhibition and inactivation of CYP2C8. [ABSTRACT FROM AUTHOR]