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To investigate whether increasing tricarboxylic acid (TCA) cycle activity and ketogenic capacity would augment fatty acid (FA) oxidation induced by the peroxisome proliferator-activated receptor-alpha (PPARα) agonist clofibrate, suckling newborn piglets (n = 54) were assigned to 8 groups following a 2 ( ± clofibrate) × 4 (glycerol succinate [SUC], triglycerides of 2-methylpentanoic acid [T2M], valeric acid [TC5] and hexanoic acid [TC6]) factorial design. Each group was fed an isocaloric milk formula containing either 0% or 0.35% clofibrate (wt/wt, dry matter basis) with 5% SUC, T2M, TC5 or TC6 for 5 d. Another 6 pigs served as newborn controls. Fatty acid oxidation was examined in fresh homogenates of liver collected on d 6 using [1-14C] palmitic acid (1 mM) as a substrate (0.265 μCi/μmol). Measurements were performed in the absence or presence of L-carnitine (1 mM) or inhibitors of 3-hydroxy-3-methylglutaryl-CoA synthase (L659699, 1.6 μM) or acetoacetate-CoA deacylase (iodoacetamide, 50 μM). Without clofibrate stimulation, 14C accumulation in CO2 was higher from piglets fed diets containing T2M and TC5 than SUC, but similar to those fed TC6. Under clofibrate stimulation, accumulation also was higher in homogenates from piglets fed TC5 than all other dietary treatments. Interactions between clofibrate and carnitine or the inhibitors were observed (P = 0.0004) for acid soluble products (ASP). In vitro addition of carnitine increased 14C-ASP (P

Introduction: Jaundice is one of the most common problems during infancy. It is believed that breast milk jaundice is one of the reasons for the persistence of jaundice after 14 days of prolonged jaundice. This study evaluates the effect of Clofibrate and phototherapy on prolonged jaundice originating from breast milk in term and healthy neonates. Materials And Methods: This double-blind clinical trial study was performed on 100 randomly divided neonates in the neonatal ward of Besat Hospital. In addition to phototherapy, the case group received a single dose of edible Clofibrate (50 mg/kg) dissolved in 2 CCs of distilled water. The control group received the same amount of distilled water as the phototherapy group. After treatment, bilirubin change rate, duration of hospitalization, and any association with gender, gestational age, hemoglobin, blood type, and Rh of neonates were determined and compared throughout the 2 groups. Results: Data analysis showed that the bilirubin reduction rate was statistically significantly higher in the case group than in the control group (P <.05). The mean duration of hospitalization and phototherapy in the case group was significantly lower than in the control group (P =.005). The bilirubin reduction rate was not affected significantly by gestational age, blood type, or Rh. Conclusion: This study's results demonstrated that Clofibrate effectively decreased bilirubin levels and shortened the duration of phototherapy and hospitalization in infants with probable breast milk jaundice. Registration: IRCT2012092910933N1 [ABSTRACT FROM AUTHOR]

To investigate the role of peroxisome proliferator-activated receptor alpha (PPARα) in carnitine status and intestinal fatty acid oxidation in neonates, a total of 72 suckled newborn piglets were assigned into 8 dietary treatments following a 2 (±0.35% clofibrate) × 4 (diets with: succinate+glycerol (Succ), tri-valerate (TC5), tri-hexanoate (TC6), or tri-2-methylpentanoate (TMPA)) factorial design. All pigs received experimental milk diets with isocaloric energy for 5 days. Carnitine statuses were evaluated, and fatty acid oxidation was measured in vitro using [1-14C]-palmitic acid (1 mM) as a substrate in absence or presence of L659699 (1.6 µM), iodoacetamide (50 µM), and carnitine (1 mM). Clofibrate increased concentrations of free (41%) and/or acyl-carnitine (44% and 15%) in liver and plasma but had no effects in the intestine. The effects on carnitine status were associated with the expression of genes involved in carnitine biosynthesis, absorption, and transportation. TC5 and TMPA stimulated the increased fatty acid oxidation rate induced by clofibrate, while TC6 had no effect on the increased fatty acid oxidation induced by clofibrate (p > 0.05). These results suggest that dietary clofibrate improved carnitine status and increased fatty acid oxidation. Propionyl-CoA, generated from TC5 and TMPA, could stimulate the increased fatty acid oxidation rate induced by clofibrate as anaplerotic carbon sources. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is associated with elevated plasma fibrinogen concentration. However, the underlying molecular mechanism for elevated plasma fibrinogen concentration in CKD patients has not yet been clarified. We recently found that HNF1α was significantly upregulated in the liver of chronic renal failure (CRF) rats, an experimental model of CKD in patients. Given that the promoter region of the fibrinogen gene possesses potential binding sites for HNF1α, we hypothesized that the upregulation of HNF1α can increase fibrinogen gene expression and consequently plasma fibrinogen concentration in the experimental model of CKD. Here, we found the coordinated upregulation of Aα-chain fibrinogen and Hnfα gene expression in the liver and elevated plasma fibrinogen concentrations in CRF rats, compared with pair-fed and control animals. Liver Aα-chain fibrinogen and HNF1α mRNAs levels correlated positively with (a) liver and plasma fibrinogen levels and (b) liver HNF1α protein levels. The positive correlation between (a) liver Aα-chain fibrinogen mRNA level, (b) liver Aα-chain fibrinogen level, and (c) serum markers of renal function suggest that fibrinogen gene transcription is closely related to the progression of kidney disease. Knockdown of Hnfα in the HepG2 cell line by small interfering RNA (siRNA) led to a decrease in fibrinogen mRNA levels. Clofibrate, an anti-lipidemic drug that reduces plasma fibrinogen concentration in humans, decreased both HNF1α and Aα-chain fibrinogen mRNAs levels in (a) the liver of CRF rats and (b) HepG2 cells. The obtained results suggest that (a) an elevated level of liver HNF1α can play an important role in the upregulation of fibrinogen gene expression in the liver of CRF rats, leading to an elevated concentration of plasma fibrinogen, a protein related to the risk of cardiovascular disease in CKD patients, and (b) fibrates can decrease plasma fibrinogen concentration through inhibition of HNF1α gene expression. [ABSTRACT FROM AUTHOR]

Metabolic syndrome (MetS) is a cluster of factors that increase the risk of developing diabetes, stroke, and heart failure. The pathophysiology of injury by ischemia/reperfusion (I/R) is highly complex and the inflammatory condition plays an important role by increasing matrix remodeling and cardiac apoptosis. Natriuretic peptides (NPs) are cardiac hormones with numerous beneficial effects mainly mediated by a cell surface receptor named atrial natriuretic peptide receptor (ANPr). Although NPs are powerful clinical markers of cardiac failure, their role in I/R is still controversial. Peroxisome proliferator-activated receptor α agonists exert cardiovascular therapeutic actions; however, their effect on the NPs' signaling pathway has not been extensively studied. Our study provides important insight into the regulation of both ANP and ANPr in the hearts of MetS rats and their association with the inflammatory conditions caused by damage from I/R. Moreover, we show that pre-treatment with clofibrate was able to decrease the inflammatory response that, in turn, decreases myocardial fibrosis, the expression of metalloprotease 2 and apoptosis. Treatment with clofibrate is also associated with a decrease in ANP and ANPr expression. [ABSTRACT FROM AUTHOR]

In neonates, bilirubin tends to be deposited in body tissues, especially the skin and mucous membranes. Jaundice is an early symptom of bilirubin excretion disorders. Therefore, the aim of this study was to investigate the effect of clofibrate on reducing neonatal jaundice. In this systematic review, international databases, including PubMed, Scopus, Web of Science, Embase, Cochrane, and Google Scholar, were searched without time and language restrictions. The reference lists of all studies ultimately included were manually searched. In the 17 articles reviewed, with a sample size of 665 people published between 2005 and 2019, the average weight of the neonates varied from 2,186 g to 4,000 g. Furthermore, the average age of neonates varied from 2 days to 9 days. Four doses of clofibrate (25, 30, 50, 100 mg/kg of neonatal body weight) were used. The bilirubin level of neonates significantly decreased in the intervention group 24, 36, 48, and 72 hours after the start of treatment. Clofibrate administration decreased total serum bilirubin, especially from the second day onwards, and also reduced hospitalization time, hospital costs, and side effects from hospitalization.

The repeated dose liver micronucleus (RDLMN) assay has been sufficiently validated in terms of the numbers and types of chemicals studied. However, it remains unclear whether aging affects assay results. The OECD Test Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents) indicates that dosing should begin as soon as feasible after weaning and in any event before 9 weeks of age. Therefore, it is particularly important to determine whether there are age-related differences between 6 and 8 weeks of age at the start of dosing when considering the possibility of integrating this assay into a 4-week repeated dose general toxicity study. We evaluated the impact of the rats' age on the RDLMN assay with three chemicals: N-nitrosodipropylamine, quinoline, and carbendazim. There were no significant age-related differences for the first two chemicals, whereas a markedly higher frequency of micronucleated hepatocytes (MNHEPs) was observed in younger rats for carbendazim. However, regardless of the age of animals, micronucleus induction was detected in all three chemicals. Combined with the previous reports on clofibrate and diethylnitrosamine, we concluded that animals of any age from 6 to 8 weeks could be used in the RDLMN assay. • MNHEPs increased with NDPA, quinoline, or carbendazim. • Age-related difference was not observed with NDPA or quinoline. • Age-related difference was observed with carbendazim. [ABSTRACT FROM AUTHOR]

Abstract Background The liver micronucleus (MN) assay is an effective and important in vivo test for detecting genotoxic compounds. In particular, the repeated-dose liver MN (RDLMN) assay which greatly facilitates incorporation of the liver MN assay into the general toxicity study has been developed. Usefulness of the RDLMN assay was appraised highly in the 7th International Workshops on Genotoxicity Testing (2017 in Tokyo) in that sufficient numbers and types of chemicals were studied and easy integration into the general toxicity study is preferred from the 3R’s point of view. However, it was pointed out that it is necessary to evaluate the effect of age at the start of 4-week repeated administration, since there are limited data, where only those of rats of 6 week of age at the start of administration are available. In this study, we conducted the 4-week RDLMN assay using rats of 6 and 8 weeks of age (at the start of administration) to investigate the effect of age on the liver MN inducibility. Clofibrate, a weak inducer of liver MN, was used in this study to detect the slight difference in the liver MN induction. Results The liver MN induced by clofibrate was detected in both rats of 6 and 8 weeks of age at the start of administration. However, the liver MN induction was lower in rats of 8 weeks of age compared to rats of 6 weeks of age at the start of administration. Conclusion These results suggest that the liver MN inducibility decreases with age. Therefore, we recommend the use of rats of 6 weeks of age at start of administration to reliably detect the liver MN induction in the RDLMN assay.

Chronic kidney disease (CKD) is associated with low-grade inflammation that activates nuclear factor–κB (NF–κB), which upregulates the expression of numerous NF–κB responsive genes, including the genes encoding IL-6, ICAM-1, VCAM-1, and MCP-1. Herein, we found the coordinated overexpression of genes encoding RelA/p65 (a subunit of NF–κB) and HNF1α in the livers of chronic renal failure (CRF) rats—an experimental model of CKD. The coordinated overexpression of RelA/p65 and HNF1α was associated with a significant increase in IL-6, ICAM-1, VCAM-1, and MCP-1 gene expressions. A positive correlation between liver RelA/p65 mRNA levels and a serum concentration of creatinine and BUN suggest that RelA/p65 gene transcription is tightly related to the progression of renal failure. The knockdown of HNF1α in the HepG2 cell line by siRNA led to a decrease in Rel A/p65 mRNA levels. This was associated with a decrease in IL-6, ICAM-1, VCAM-1, and MCP-1 gene expressions. The simultaneous repression of HNF-1α and RelA/p65 by clofibrate is tightly associated with the downregulation of IL-6, ICAM-1, VCAM-1, and MCP-1 gene expression. In conclusion, our findings suggest that NF–κB could be a downstream component of the HNF1α-initiated signaling pathway in the livers of CRF rats. [ABSTRACT FROM AUTHOR]

In neonates, bilirubin tends to be deposited in body tissues, especially the skin and mucous membranes. Jaundice is an early symptom of bilirubin excretion disorders. Therefore, the aim of this study was to investigate the effect of clofibrate on reducing neonatal jaundice. In this systematic review, international databases, including PubMed, Scopus, Web of Science, Embase, Cochrane, and Google Scholar, were searched without time and language restrictions. The reference lists of all studies ultimately included were manually searched. In the 17 articles reviewed, with a sample size of 665 people published between 2005 and 2019, the average weight of the neonates varied from 2,186 g to 4,000 g. Furthermore, the average age of neonates varied from 2 days to 9 days. Four doses of clofibrate (25, 30, 50, 100 mg/kg of neonatal body weight) were used. The bilirubin level of neonates significantly decreased in the intervention group 24, 36, 48, and 72 hours after the start of treatment. Clofibrate administration decreased total serum bilirubin, especially from the second day onwards, and also reduced hospitalization time, hospital costs, and side effects from hospitalization. [ABSTRACT FROM AUTHOR]

Background: No studies, to the best of our knowledge, have been conducted on the effect of Clofibrate in reducing hyperbilirubinemia in preterm infants. Therefore, this study aimed at investigating the therapeutic effect of Clofibrate in treating hyperbilirubinemia of preterm neonates. Methods: This clinical trial was performed from April 4 to December 20, 2019, on neonates in Hamadan in western Iran. The allocation remained concealed to the researcher, neonates’ parents, and analyzer during the study. A dose of Clofibrate of 25 kg/mg was given on the first day of hospitalization. The neonates in the placebo group received the oral placebo 25 kg/mg in the same way as the oral Clofibrate. The data were analyzed using SPSS 16 with P-value < 0.05. Results: No statistically significant difference was observed in the baseline characteristics of the two groups based on the neonate’s age and gender, delivery method, and gestational age. The prescription of Clofibrate significantly reduced the duration of hospitalization (p= 0.002) and phototherapy (p= 0.001). Prescribing a single oral dose of Clofibrate (25 mg/Kg) along with phototherapy in preterm neonates significantly reduced total serum bilirubin levels at 24 and 48 hours after treatment compared with phototherapy alone (p= 0.001). However, this association was not significant in admission (p= 0.095). Conclusion: The findings of this study showed the effect of Clofibrate in treating hyperbilirubinemia of preterm neonates. In addition, prescribing Clofibrate significantly reduced the duration of hospitalization and phototherapy.

Chronic kidney disease (CKD) is associated with elevated plasma fibrinogen concentration. However, the underlying molecular mechanism for elevated plasma fibrinogen concentration in CKD patients has not yet been clarified. We recently found that HNF1α was significantly upregulated in the liver of chronic renal failure (CRF) rats, an experimental model of CKD in patients. Given that the promoter region of the fibrinogen gene possesses potential binding sites for HNF1α, we hypothesized that the upregulation of HNF1α can increase fibrinogen gene expression and consequently plasma fibrinogen concentration in the experimental model of CKD. Here, we found the coordinated upregulation of Aα-chain fibrinogen and Hnfα gene expression in the liver and elevated plasma fibrinogen concentrations in CRF rats, compared with pair-fed and control animals. Liver Aα-chain fibrinogen and HNF1α mRNAs levels correlated positively with (a) liver and plasma fibrinogen levels and (b) liver HNF1α protein levels. The positive correlation between (a) liver Aα-chain fibrinogen mRNA level, (b) liver Aα-chain fibrinogen level, and (c) serum markers of renal function suggest that fibrinogen gene transcription is closely related to the progression of kidney disease. Knockdown of Hnfα in the HepG2 cell line by small interfering RNA (siRNA) led to a decrease in fibrinogen mRNA levels. Clofibrate, an anti-lipidemic drug that reduces plasma fibrinogen concentration in humans, decreased both HNF1α and Aα-chain fibrinogen mRNAs levels in (a) the liver of CRF rats and (b) HepG2 cells. The obtained results suggest that (a) an elevated level of liver HNF1α can play an important role in the upregulation of fibrinogen gene expression in the liver of CRF rats, leading to an elevated concentration of plasma fibrinogen, a protein related to the risk of cardiovascular disease in CKD patients, and (b) fibrates can decrease plasma fibrinogen concentration through inhibition of HNF1α gene expression.

Background: The liver micronucleus (MN) assay is an effective and important in vivo test for detecting genotoxic compounds. In particular, the repeated-dose liver MN (RDLMN) assay which greatly facilitates incorporation of the liver MN assay into the general toxicity study has been developed. Usefulness of the RDLMN assay was appraised highly in the 7th International Workshops on Genotoxicity Testing (2017 in Tokyo) in that sufficient numbers and types of chemicals were studied and easy integration into the general toxicity study is preferred from the 3R's point of view. However, it was pointed out that it is necessary to evaluate the effect of age at the start of 4-week repeated administration, since there are limited data, where only those of rats of 6 week of age at the start of administration are available. In this study, we conducted the 4-week RDLMN assay using rats of 6 and 8 weeks of age (at the start of administration) to investigate the effect of age on the liver MN inducibility. Clofibrate, a weak inducer of liver MN, was used in this study to detect the slight difference in the liver MN induction. Results: The liver MN induced by clofibrate was detected in both rats of 6 and 8 weeks of age at the start of administration. However, the liver MN induction was lower in rats of 8 weeks of age compared to rats of 6 weeks of age at the start of administration. Conclusion: These results suggest that the liver MN inducibility decreases with age. Therefore, we recommend the use of rats of 6 weeks of age at start of administration to reliably detect the liver MN induction in the RDLMN assay. [ABSTRACT FROM AUTHOR]

Background: No studies, to the best of our knowledge, have been conducted on the effect of Clofibrate in reducing hyperbilirubinemia in preterm infants. Therefore, this study aimed at investigating the therapeutic effect of Clofibrate in treating hyperbilirubinemia of preterm neonates. Methods: This clinical trial was performed from April 4 to December 20, 2019, on neonates in Hamadan in western Iran. The allocation remained concealed to the researcher, neonates’ parents, and analyzer during the study. A dose of Clofibrate of 25 kg/mg was given on the first day of hospitalization. The neonates in the placebo group received the oral placebo 25 kg/mg in the same way as the oral Clofibrate. The data were analyzed using SPSS 16 with Pvalue < 0.05. Results: No statistically significant difference was observed in the baseline characteristics of the two groups based on the neonate’s age and gender, delivery method, and gestational age. The prescription of Clofibrate significantly reduced the duration of hospitalization (p= 0.002) and phototherapy (p= 0.001). Prescribing a single oral dose of Clofibrate (25 mg/Kg) along with phototherapy in preterm neonates significantly reduced total serum bilirubin levels at 24 and 48 hours after treatment compared with phototherapy alone (p= 0.001). However, this association was not significant in admission (p= 0.095). Conclusion: The findings of this study showed the effect of Clofibrate in treating hyperbilirubinemia of preterm neonates. In addition, prescribing Clofibrate significantly reduced the duration of hospitalization and phototherapy. [ABSTRACT FROM AUTHOR]

Covalent organic nanospheres are new kind of nanospherical polymer with large specific surface area, uniform morphology, and excellent chemical and thermal stability. This material can be fabricated by a facile and rapid room temperature solution‐phase strategy. In this work, magnetic nanoparticles were attached to the surface of covalent organic nanospheres, and the obtained composites were used for the extraction of blood lipid regulators such as clofibrate and fenofibrate. These composites were characterized with Fourier‐transformed infrared spectroscopy, X‐ray photoelectron spectroscopy, and transmission electron microscopy. Several parameters that might affect the extraction efficiency including acetonitrile content, pH value, extraction time, and sample volume were investigated. Under optimum conditions, the proposed analytical method showed high extraction efficiency toward clofibrate and fenofibrate with enrichment factors between 60 and 83. This method exhibited outstanding analytical performance with wide linear range and excellent reproducibility and had low limits of detection in the range of 0.02–0.03 ng/mL. This method was also applied to the detection of clofibrate and fenofibrate in lake water samples, and good recoveries in the range of 92.6–112.6% was obtained. [ABSTRACT FROM AUTHOR]

Background and aim: Off‐label use of fibrates in patients with cholestatic liver diseases results in improved biochemical parameters and pruritus; however, their safety in this population has been a concern. This study summarizes safety data for fibrates when used for treatment of cholestatic liver diseases. Methods: A systematic review of published studies evaluating the use of fibrates for treatment of primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) was performed. Electronic databases were searched up to December 2019 for published studies evaluating treatment outcomes associated to fibrates for these 2 diseases. Results: A total of 37 studies were identified, including 31 for PBC and 6 for PSC, with a total of 1107 unique patients treated with fibrates ± ursodeoxycholic acid (UDCA). Most studies evaluated fenofibrate and bezafibrate, and only 1 study evaluated pemafibrate. There were no studies evaluating gemfibrozil or clofibrate. The most commonly reported adverse events (AEs) were gastrointestinal and musculoskeletal. Elevations of aminotransferases and serum creatinine were reported more commonly in patients treated with UDCA plus fibrates versus UDCA monotherapy. Conclusions: Fibrates appear to be safe and well tolerated in patients with PBC, with a low frequency of AEs. There are scarce data about the safety of these agents for treatment of PSC. [ABSTRACT FROM AUTHOR]

Background: Neonatal jaundice is a prevalent disease that causes many complications, including kernicterus and even death. Previous studies have shown that clofibrate as an aryloxy isobutyric acid derivate can be effectively applied for the treatment of neonatal jaundice. Thus, this review was carried out to investigate the effects and mechanism of action of clofibrate on neonatal jaundice. Methods: The keywords such as “Clofibrate” in combination with “Neonatal jaundice” or “Neonatal hyperbilirubinemia” or “Newborn Jaundice” were used to search for relevant publications indexed in the Institute for Scientific Information (ISI), Scopus, PubMed, and Google Scholar databases. Finally, after reviewing the studies, 24 papers were included in this study. Results: Results showed that the processes of albumin-bound bilirubin transfer to the hepatocytes, hepatic uptake, and storage via ligandin, hepatic conjugation via uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), conjugation into the bile via MRP2 represent the main action mechanism of clofibrate that turns it into the bilirubin conjugates and expels it from the bile. Besides, clofibrate has been shown to reduce the level of Total Serum Bilirubin (TSB) in infants even at a dosage of 25 mg/kg without leaving side effects. Conclusions: The results of this review revealed that clofibrate effectively reduces TSB in short-term usage and can even have a promising effect at the dosage of 25 mg/kg in full-term infants. Most studies have shown this property over a short period in term infants, and there is no evidence about long-term usage in this regard.

Fluoride is an environmental contaminant that is ubiquitously present in air, water, and soil. It is commonly added in minute quantity to drinking water, toothpaste, and mouth rinses to prevent tooth decay. Epidemiological findings have demonstrated that exposure to fluoride induced neurodevelopmental toxicity, developmental neurotoxicity, and motor disorders. The neuroprotective effect of clofibrate, a peroxisome proliferator‐activated receptor alpha agonist, was investigated in the present study. Forty male Wistar rats were used for this study and randomly grouped into 10 rats per group as control, sodium fluoride (NaF) alone (300 ppm), NaF plus clofibrate (250 mg/kg), and NaF plus lisinopril (10 mg/kg), respectively, for 7 days. NaF was administered in drinking water while clofibrate and lisinopril were administered by oral gavage. Markers of neuronal inflammation and oxidative stress, acetylcholinesterase activity, and neurobehavioral (hanging wire and open field) tests were performed. Immunohistochemistry was performed on brain tissues, and they were probed with glial fibrillary acidic protein, ionized calcium‐binding adaptor molecule 1, and cerebellar Ca2+‐binding protein calbindin‐D28k. The results showed that NaF significantly increased of oxidative stress and neuroinflammation and inhibited AChE activity. Immunostaining showed reactive astrocytes, microgliosis, loss of dendritic spines, and arborization in Purkinje cells in rats administered only NaF. Neurobehavioral results showed that cotreatment of NaF with clofibrate improved muscular strength and locomotion, reduced anxiety, and significantly reduced astrocytic count. Overall, cotreatment of NaF with either clofibrate or lisinopril showed neuroprotective effects by mitigating neuronal inflammation and oxidative and motor incoordination. Hence, clofibrate could be seen as a novel drug candidate against neurodegeneration and motor disorders. [ABSTRACT FROM AUTHOR]

This study was conducted to determine the effect of purgative Manna and clofibrate on unconjugated hyperbilirubinemia of term neonates. In this randomized clinical trial study, sixty neonates suffering from unconjugated hyperbilirubinemia were evaluated. The neonates were divided into three groups using balanced block randomization. Group A (control group-received only phototherapy), group B (intervention group-received purgative Manna and phototherapy) and group C (intervention group-received clofibrate and phototherapy). After the intervention, the amount of serum bilirubin reduction was compared between groups. There was no significant difference among group A, B, and C in terms of serum bilirubin reduction in 24, 48 and 72 hours after starting the intervention (P>0.05). The hospital stays in the control group was significantly longer than the intervention groups (P

This study was conducted to determine the effect of purgative Manna and clofibrate on unconjugated hyperbilirubinemia of term neonates. In this randomized clinical trial study, sixty neonates suffering from unconjugated hyperbilirubinemia were evaluated. The neonates were divided into three groups using balanced block randomization. Group A (control group-received only phototherapy), group B (intervention group-received purgative Manna and phototherapy) and group C (intervention group-received clofibrate and phototherapy). After the intervention, the amount of serum bilirubin reduction was compared between groups. There was no significant difference among group A, B, and C in terms of serum bilirubin reduction in 24, 48 and 72 hours after starting the intervention (P>0.05). The hospital stays in the control group was significantly longer than the intervention groups (P<0.05). No side effects were observed related to using purgative Mienna and clofibrate. The present study showed that prescribing of purgative Manna and clofibrate has no effect on reduction of serum bilirubin level in term neonates with unconjugated hyperbilirubinemia. Thus, it seems that the administration of these drugs is not necessary. Further studies in this regard are recommended. [ABSTRACT FROM AUTHOR]

The Pig‐a assay is an emerging and promising in vivo method to determine mutagenic potential of chemicals. Since its development in 2008, remarkable progress has been made in harmonizing and characterizing the test procedures, primarily using known mutagenic chemicals. The purpose of the present study was to evaluate specificity of the Pig‐a assay using two nongenotoxic and well‐characterized rodent liver carcinogens, phenobarbital and clofibrate, in male F344/DuCrl rats. Daily oral administration of phenobarbital or clofibrate at established hepatotoxic doses for 28 days resulted in substantial hepatic alterations, however, did not increase the frequency of Pig‐a mutation markers (RETCD59‐ and RBCCD59‐) compared to vehicle control or pre‐exposure (Day −5) mutant frequencies. These results are consistent with the existing literature on the nonmutagenic mode of action (MoA) of phenobarbital and clofibrate liver tumors. The present study contributes to the limited, but expanding evidence on the specificity of the Pig‐a assay and further for the investigations of carcinogenic MoAs, i.e., mutagenic or nonmutagenic potential of chemicals. Environ. Mol. Mutagen. 60:42–46, 2019. © 2018 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background: Clofibrate is a pharmacological agent, which affects the lipid metabolism. This compound could be involved in bilirubin accumulation and excretion process. Therefore, this study aimed to evaluate the effect of oral clofibrate intake on total serum bilirubin (TSB) of neonates hospitalized at Khatam Hospital. Methods: This clinical trial was conducted on 73 neonates with hyperbilirubinemia. Samples were divided into clofibrate (n=41) and control (n=32) groups. In the Clofibrate group, samples were given a single oral dose of 100 mg/kg clofibrate, whereas the control group received distilled water in an equal amount and color as placebo. Birth weight, type of delivery, gender, age and primary TSB level were recorded prior to the intervention and TSB was measured 24, 48 and 72 hours after the intervention. Results: In this study,no significant difference was observed between the groups on the first and third day of intervention in terms of mean TSB in neonates. However, a significant reduction was found on the second day in mean TSB of neonates, who received clofibrate (P=0.04). Conclusion: According to the results of this study, application of clofibrate was associated with faster alleviation of mean TSB and shorter duration of hospital stay without major side effects. Therefore, it is recommended that clofibrate be only used for clinical management of neonatal hyperbilirubinemia.

Background: hyperbilirubinemia develop in all newborns and resolves within the first several weeks after birth. Clofibrate is planned for management of indirect hyperbilirubinemia Aim: to evaluate Benefit of Clofibrate on indirect hyperbilirubinemia in newborn. Patients and Methods: this is a case- control study of 100 neonates on clofibrate and 100 neonates control groups, both with jaundice enrolled in fifty sex months from June 2008- March 2013 in the Tikrit hospital and personal doctor's office ,Clofibrate group received clofibrate 100mg/kg.Evaluation of TSB reduction at different intervals regarding admission day,after 12-hr, 24-hr and4-day compare with control Results:The12-hr,24-hr,4-days reduction in TSB of clofibrate group were higher19.74±1.72mg/dl , 15.49±1.16mg/dl, 10.4±1.7mg/dL than in control group 17.11 ± 2.02 mg/dL, 16.09± 1.96mg/dL, 13.6±1.52mg/dL respectively with overall significant (P = .031944) The diminished need for phototherapy (P = 0.0198) and hospitalization time (P = 0.025) in clofibrate group were significantly important compare with control group Conclusion: Clofibrate (100mg) solitary dose used in neonates safely because decreasing bilirubin additionally reduce phototherapy , hospitalization time in neonates appeared within 24 hr and full action of clofibrate appeared between 24hr up to 96 hr.

Background: Neonatal jaundice is a common problem that can result in serious neurological side effect such as Kern icterus. Several drugs are used to prevent neonatal jaundice. The effect of clofibrate in the prevention of hyperbilirubi-nemia in healthy term neonates has not been paid attention to. This study aimed to evaluate the preventive effect of clofibrate on neonatal jaundice in term neonates. Methods: This clinical trial was conducted on 80 healthy newborns randomly divided in to cases and control groups. The case group received clofibrate (50 mg/kg of body weight) orally in the first hour after birth and after the first period of breastfeeding. Serum bilirubin levels were measured in cord blood and again at 24, 48 and 72 hours after birth in both groups and were compared. Babies with clear jaundice on the first day, direct neonatal jaundice>1 mg/dl, sick infants, and infants of mothers treated with phenobarbital and preterm infants weighing less than 2500 gr were excluded. Results: The mean bilirubin level in cord blood and its level at 24, 48 and 72 hours after birth in control groups were 1.99±0.46, 2.88±0.88, 5.94±1.15, 7.65±1.69, respectively and in the case group were 2.12±0.75, 2.89±0.95, 5.8±1.16, 7.18±1.57, respectively. Thus, the mean bilirubin in the case group is lower, but it was not statistically significant. Also, sex distribution, Rh-blood group incompatibility and G6PD deficiency in both groups showed no significant difference. Conclusions: Our results showed that prophylactic clofibrate application reduced neonatal hyperbilirubinemia, but wasn’t statistically significant.

Lipid metabolism involves complex pathways, which are regulated in a similar way across vertebrates. Hormonal and hypolipidemic deregulations cause lipid imbalance from fish to humans, but the underlying mechanisms are far from understood. This study explores the potential of using juvenile brown trout to evaluate the in vivo interferences caused by estrogenic (17α-ethinylestradiol – EE2), androgenic (testosterone – T), and hypolipidemic (clofibrate – CLF) compounds in lipidic and/or peroxisomal pathways. Studied endpoints were from blood/plasma biochemistry, plasma fatty acid profile, ultrastructure of hepatocytes and abundance of their peroxisomes to mRNA expression in the liver. Both T and CLF caused minimal effects when compared to EE2. Estrogenized fish had significantly higher hepatosomatic indexes, increased triglycerides and very-low density lipoproteins (VLDL) in plasma, compared with solvent control. Morphologically, EE2 fish showed increased lipid droplets in hepatocytes, and EE2 and T reduced volume density of peroxisomes in relation to the hepatic parenchyma. Polyunsaturated fatty acids (PUFA) in plasma, namely n−3 PUFA, increased with EE2. EE2 animals had increased mRNA levels of vitellogenin A (VtgA), estrogen receptor alpha (ERα), peroxisome proliferator-activated receptor alpha (PPARα), PPARαBa and acyl-CoA long chain synthetase 1 (Acsl1), while ERβ-1, acyl-CoA oxidase 1–3I (Acox1–3I), Acox3, PPARγ, catalase (Cat), urate oxidase (Uox), fatty acid binding protein 1 (Fabp1) and apolipoprotein AI (ApoAI) were down-regulated. In summary, in vivo EE2 exposure altered lipid metabolism and peroxisome dynamics in brown trout, namely by changing the mRNA levels of several genes. Our model can be used to study possible organism-level impacts, viz. in gonadogenesis. [ABSTRACT FROM AUTHOR]

Purpose: Fibrates are drugs widely used for the treatment of hyperlipidemic disorders. Previous studies on a novel analogue of clofibrate, called silafibrate, have shown good lipid lowering effects. This study was designed to assess the role of silafibrate as a peroxisome proliferator-activated receptors (PPARs) agonist on sperm health and spermatogenesis in adult male rats. Material and Methods: Seventy male Wistar rats were randomly allocated into 7 groups: Cl-10, Cl-20, and Cl-40 mg/kg/day (clofibrate); Si-10, Si-20, and Si-40 mg/kg/day (silafibrate); and C, control. After a 28-day treatment, all rats were euthanized. Blood samples were taken for determination of testosterone, total antioxidant capacity, levels of malondialdehyde, and oxidized low-density lipoprotein. Reproductive organs were dissected and spermatozoa collected from the epididymis for analysis. Result: Sperm parameters (count, motility, viability, and morphology) and total serum testosterone decreased significantly in clofibrate-treated (20 and 40 mg/kg) rats (P < 0.05) as compared with normal rats. Conclusion: We conclude that PPARs agonists have significant adverse effect on sperm viability, motility, and total serum testosterone, and could be harmful for sperm parameters and male reproductive function in rats. [ABSTRACT FROM AUTHOR]

Fibrates and their receptor, namely peroxisome proliferator-activated receptor a (PPARa), have been reported to regulate bile acid (BA) synthesis and transport. However, the effect of fibrate treatment and PPARa activation on BA homeostasis remains controversial. In this study, both wild-type (WT) and PPARa-null male mice were treated with clofibrate (CLOF) for 4 days to evaluate the effects of short-termPPARa activation on BA homeostasis. Although a decrease in total BAs (RBAs) was observed in livers of CLOF-treated WT mice, it was not observed in PPARa-null mice. CLOF-mediated decrease in RBAs in the liver was not likely due to the reduction in BA synthesis or BA uptake, as evidenced by an increase in the BA synthetic enzyme (Cyp7a1) and 2 BA uptake transporters (Na (+)-taurocholate cotransporting polypeptide [Ntcp] and organic anion transporting polypeptide [Oatp]1b2). Instead, the decrease in liver BAs by CLOF is largely a result of increased biliary excretion of BAs, which was associated with a significant induction of the canalicular efflux transporter (bile salt export pump [Bsep]) in the liver. The PPARa-mediated increase in Cyp7a1 in CLOF-treatedWT mice was not due to farnesoid X receptor (Fxr)-small heterodimer partner (Shp) signaling in the liver, but due to suppression of Fxr- fibroblast growth factor15 signaling in the ileum. Additionally, CLOF also suppressed intestinal BA transporters (apical sodium-dependent bile acid transporter and organic solute transporterb) and cholesterol efflux transporters (Abcg5 and Abcg8) in a PPARadependent manner. In summary, this study provides the first comprehensive analysis on the effect of a short-term CLOF treatment on BA homeostasis, and revealed an essential role of PPARa in regulating BA synthesis, transport and signaling. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the effects of peroxisome proliferator-activated receptor α (PPARα) activation by clofibrate on both mitochondrial and peroxisomal fatty acid oxidation in the developing kidney. Ten newborn pigs from 5 litters were randomly assigned to two groups and fed either 5 mL of a control vehicle (2% Tween 80) or a vehicle containing clofibrate (75 mg/kg body weight, treatment). The pigs received oral gavage daily for three days. In vitro fatty acid oxidation was then measured in kidneys with and without mitochondria inhibitors (antimycin A and rotenone) using [1-14C]-labeled oleic acid (C18:1) and erucic acid (C22:1) as substrates. Clofibrate significantly stimulated C18:1 and C22:1 oxidation in mitochondria (p < 0.001) but not in peroxisomes. In addition, the oxidation rate of C18:1 was greater in mitochondria than peroxisomes, while the oxidation of C22:1 was higher in peroxisomes than mitochondria (p < 0.001). Consistent with the increase in fatty acid oxidation, the mRNA abundance and enzyme activity of carnitine palmitoyltransferase I (CPT I) in mitochondria were increased. Although mRNA of mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase (mHMGCS) was increased, the β-hydroxybutyrate concentration measured in kidneys did not increase in pigs treated with clofibrate. These findings indicate that PPARα activation stimulates renal fatty acid oxidation but not ketogenesis. [ABSTRACT FROM AUTHOR]

Icariin is effective in the treatment of hyperlipidemia. To understand the effect of icariin on lipid metabolism, effects of icariin on PPARα and its target genes were investigated. Mice were treated orally with icariin at doses of 0, 100, 200, and 400 mg/kg, or clofibrate (500 mg/kg) for five days. Liver total RNA was isolated and the expressions of PPARα and lipid metabolism genes were examined. PPARα and its marker genes Cyp4a10 and Cyp4a14 were induced 2-4 fold by icariin, and 4-8 fold by clofibrate. The fatty acid (FA) binding and co-activator proteins Fabp1, Fabp4 and Acsl1 were increased 2-fold. The mRNAs of mitochondrial FA β-oxidation enzymes (Cpt1a, Acat1, Acad1 and Hmgcs2) were increased 2-3 fold. The mRNAs of proximal β-oxidation enzymes (Acox1, Ech1, and Ehhadh) were also increased by icariin and clofibrate. The expression of mRNAs for sterol regulatory element-binding factor-1 (Srebf1) and FA synthetase (Fasn) were unaltered by icariin. The lipid lysis genes Lipe and Pnpla2 were increased by icariin and clofibrate. These results indicate that icariin is a novel PPARα agonist, activates lipid metabolism gene expressions in liver, which could be a basis for its lipid-lowering effects and its beneficial effects against diabetes.

Myocardial infarction (MI) initiates an inflammatory response that promotes both beneficial and deleterious effects. The early response helps the myocardium to remove damaged tissue; however, a prolonged later response brings cardiac remodeling characterized by functional, metabolic, and structural pathological changes. Current pharmacological treatments have failed to reverse ischemic-induced cardiac damage. Therefore, our aim was to study if clofibrate treatment was capable of decreasing inflammation and apoptosis, and reverse ventricular remodeling and MI-induced functional damage. Male Wistar rats were assigned to (1) Sham coronary artery ligation (Sham) or (2) Coronary artery ligation (MI). Seven days post-MI, animals were further divided to receive vehicle (V) or clofibrate (100 mg/kg, C) for 7 days. The expression of IL-6, TNF-α, and inflammatory related molecules ICAM-1, VCAM-1, MMP-2 and -9, nuclear NF-kB, and iNOS, were elevated in MI-V. These inflammatory biomarkers decreased in MI-C. Also, apoptotic proteins (Bax and pBad) were elevated in MI-V, while clofibrate augmented anti-apoptotic proteins (Bcl-2 and 14-3-3ε). Clofibrate also protected MI-induced changes in ultra-structure. The ex vivo evaluation of myocardial functioning showed that left ventricular pressure and mechanical work decreased in infarcted rats; clofibrate treatment raised those parameters to control values. Echocardiogram showed that clofibrate partially reduced LV dilation. In conclusion, clofibrate decreases cardiac remodeling, decreases inflammatory molecules, and partly preserves myocardial diameters.

We tested the hypothesis that prenatal administration of PPARα agonist clofibrate may permanently increase browning capacity of developing white adipose tissue (WAT). Pregnant C57BL/6J mice were fed a basal diet, without (C) or with 0.5% clofibrate (CF, a PPARα agonist) throughout pregnancy. After parturition, only male offspring were used; all suckled their mothers (who were eating the C diet) and after weaning, they ate a standard chow diet for 4 wk, followed by a high-fat diet (HFD) for 5 wk. Administration of CF up-regulated serum concentrations and hepatic expression of FGF21 in fetuses, with a return to basal levels after CF withdrawal. At postnatal day 84 (P84), CF-offspring had significantly higher expression of thermogenic genes (Ucp1, Cidea, Ppara Ppargc1a, Cpt1b) and UCP1 protein levels in response to HFD in inguinal fat, but not in retroperitoneal (combined with perirenal) or epididymal fat. Based on UCP1 levels in inguinal fat on P7, P14, and P21, appearance of the transient brown-adipocyte phenotype seemed to be hastened by CF exposure. We concluded that giving CF to pregnant mice programmed greater HFD-induced WAT browning in subcutaneous, but not in visceral fat, in their male offspring at adulthood. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy of oral clofibrate as an adjunct to phototherapy for unconjugated hyperbilirubinemia in term neonates.Methods: This randomized controlled trial was done in the level III neonatal intensive care unit (NICU) of a tertiary care hospital. Ninety term neonates with unconjugated hyperbilirubinemia with serum bilirubin 15-25 mg/dl were randomized to either intervention group (single dose of clofibrate in a dose of 50 mg/kg prior to starting phototherapy) or standard care group (only phototherapy). Primary outcome was absolute fall in bilirubin by 48 h. Secondary outcomes were duration of phototherapy, absolute fall in bilirubin levels at 12, 24, 36, 48 h, need for exchange transfusion and incidence of side-effects.Results: After 48 h of intervention, significantly lower bilirubin levels were noted in the intervention group compared to standard care group with a mean difference of 7 mg/dl (95% CI 6.7 mg/dl to 7.2 mg/dl). Duration of phototherapy required was less in the intervention group compared to standard care group with mean difference of 23.82 h (95% CI 30.46 h to 17.18 h). Exchange transfusion was needed for 4 neonates in the standard care group and none in the intervention group. No side-effects were noted with clofibrate.Conclusions: Single dose clofibrate prior to starting phototherapy in term neonates with uncomplicated unconjugated hyperbilirubinemia reduces the duration of phototherapy significantly. [ABSTRACT FROM AUTHOR]

Clofibrate is a known rodent hepatotoxicant classically associated with hepatocellular hypertrophy and increased serum activities of cellular alanine aminotransferase/aspartate aminotransferase (ALT/AST) in the absence of microscopic hepatocellular degeneration. At toxic dose, clofibrate induces liver and skeletal muscle injury. The objective of this study was to assess novel liver and skeletal muscle biomarkers following clofibrate administration in Wistar rats at different dose levels for 7 days. In addition to classical biomarkers, liver injury was assessed by cytokeratin 18 (CK18) cleaved form, high-mobility group box 1, arginase 1 (ARG1), microRNA 122 (miR-122), and glutamate dehydrogenase. Skeletal muscle injury was evaluated with fatty acid binding protein 3 (Fabp3) and myosin light chain 3 (Myl3). Clofibrate-induced hepatocellular hypertrophy and skeletal muscle degeneration (type I rich muscles) were noted microscopically. CK, Fabp3, and Myl3 elevations correlated to myofiber degeneration. Fabp3 and Myl3 outperformed CK for detection of myofiber degeneration of minimal severity. miR-122 and ARG1 results were significantly correlated and indicated the absence of liver toxicity at low doses of clofibrate, despite increased ALT/AST activities. Moreover, combining classical and novel biomarkers (Fabp3, Myl3, ARG1, and miR-122) can be considered a valuable strategy for differentiating increased transaminases due to liver toxicity from skeletal muscle toxicity. [ABSTRACT FROM AUTHOR]

Background: Proteinuria plays an essential role in the progression of tubulointerstitial damage, which causes end-stage renal disease. An increased load of fatty acids bound to albumin reabsorbed into proximal tubular epithelial cells (PTECs) contributes to tubulointerstitial damage. Fibrates, agonists of peroxisome proliferator-activated receptor α (PPARα), have renoprotective effects against proteinuria whereas the effects of these compounds on fatty acid metabolism in the kidney are still unknown. Therefore, the present study examined whether the renoprotective effects of clofibrate were associated with improvement of fatty acid metabolism in puromycin aminonucleoside (PAN)-induced nephrotic rats. Methods: Rats were allocated to the control, PAN or clofibrate-treated PAN group. Biochemical parameters, renal injury and changes in fatty acid metabolism were studied on day14. Results: PAN increased proteinuria, lipid accumulation in PTECs, excretions of N-acetyl-β- d-glucosaminidase (NAG) and 8-hydroxydeoxyguanosine (8OHdG) and the area of caspase 3-positive tubular cells. It decreased renal expressions of medium-chain acyl-CoA dehydrogenase (MCAD), cytochrome P450 (CYP)4A, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and estrogen-related receptor α (ERRα) without change of the expression of PPARα. Clofibrate reduced proteinuria, lipid accumulation, NAG excretion and the area of caspase 3-positive tubular cells. However, albumin excretion was not reduced and 8OHdG excretion was increased. Clofibrate minimized changes in MCAD, CYP4A, PGC-1α and ERRα expressions with increased PPARα, very long-chain acyl-CoA dehydrogenase (VLCAD) and long-chain acyl-CoA dehydrogenase (LCAD) expressions. Conclusion: Clofibrate is protective against renal lipotoxicity in PAN nephrosis. This study indicates that clofibrate has renoprotective effects through maintaining fatty acid metabolism in the kidney of PAN-induced nephrotic rats. [ABSTRACT FROM AUTHOR]

Oily liquid drugs are not convenient for oral administration. We developed a powder containing clofibrate (CF), a model of an oily drug, using aminoalkyl methacrylate copolymer (EPO) or methacrylic acid copolymer (L100). CF or a mixture of CF and soybean oil was emulsified with EPO or L100 aqueous solution. Using a high-pressure homogenizer, a stable emulsion was obtained, and a powder was then obtained by lyophilization of the emulsion. The content of CF in the powder depended on the formulation, with the highest contents being 24.6% and 27.1% for EPO and L100, respectively. The incorporation ratio of CF was higher for L100 than for EPO. The powder using EPO was sticky because of leaked CF and the low glass transition temperature of EPO. The powder using L100 was a typical powder obtained by lyophilization. The leakage of CF from the powder was <2%, lower than for EPO powder. The dissolution of CF from powder using EPO was fast, regardless of the pH of the medium, but the powder using L100 showed enteric-soluble characteristics, indicating that CF is well incorporated in L100. [ABSTRACT FROM AUTHOR]

Background and Aims: Clofibrate, an established PPARα ligand, has recently been shown to have anticancer activity yet its mechanisms of action remain to be characterized. This study examined the effect of clofibrate on heme oxygenase-1 (HO-1) gene expression in A2780 (human ovarian cancer) and DU145 (human prostate cancer) cells. Methods and Results: We demonstrate that clofibrate induces HO-1 expression in a concentration- and time-dependent manner. The induction of HO-1 by clofibrate was detected at both mRNA and protein levels and the HO-1 gene promoter activity was also dramatically induced by clofibrate, indicating that clofibrate up-regulates HO-1 gene transcription. Surprisingly, the induction of HO-1 by clofibrate was mediated by the Nrf2 signaling pathway, not by the PPARα pathway. This was primarily demonstrated by siRNA knockdown of Nrf2 expression that significantly attenuated clofibrate-induced HO-1 gene transcription, and siRNA knockdown of PPARα that had no effect on clofibrate-induced HO-1 promoter activity. Furthermore, deletion of the antioxidant response elements (AREs) in the HO-1 gene promoter diminished clofibrate-induced HO-1 transcription and deletion of the PPAR response elements (PPREs) had no such effect. Likewise, application of PPARα antagonists had no effect on clofibrate-induced HO-1 expression. Conclusion: Clofibrate induces HO-1 gene expression in cancer cells through a PPARα-independent mechanism and the Nrf2 signaling pathway is indispensible for this induction.