Peroxisome proliferator-activated receptors (PPAR) downregulate the expression of pro-inflammatory molecules in an experimental model of myocardial infarction.

Myocardial infarction (MI) has been associated with an inflammatory response and a rise in TNF-α, interleukin (IL)-1ß, and IL-6. Peroxisome proliferator-activated receptors (PPARs) promote a decreased expression of inflammatory molecules. We aimed to study whether PPAR stimulation by clofibrate decreases inflammation and reduces infarct size in rats with MI. Male Wistar rats were randomized into 3 groups: control, MI + vehicle, and MI + clofibrate (100 mg/kg). Treatment was administered for 3 consecutive days, previous to 2 h of MI. MI induced an increase in protein expression, mRNA content, and enzymatic activity of inducible nitric oxide synthase (iNOS). Additionally, MI incited an increased expression of matrix metalloproteinase (MMP)-2 and MMP-9, intercellular adhesion molecule (ICAM)-1, and IL-6. MI also elevated the nuclear content of nuclear factor-κB (NF-κB) and decreased IκB, both in myocyte nuclei and cytosol. Clofibrate treatment prevented MI-induced changes in iNOS, MMP-2 and MMP-9, ICAM-1, IL-6, NF-κB, and IκB. Infarct size was smaller in clofibrate-treated rats compared to MI-vehicle animals. In silico analysis exhibited 3 motifs shared by genes from renin-angiotensin system, PPARα, iNOS, MMP-2 and MMP-9, ICAM-1, and VCAM-1, suggesting a cross regulation. In conclusion, PPARα-stimulation prevents overexpression of pro-inflammatory molecules and preserves viability in an experimental model of acute MI.

Fibrates for secondary prevention of cardiovascular disease and stroke.

BACKGROUND: Fibrates are a class of drugs characterised by mainly lowering high triglyceride, raising high-density lipoprotein (HDL) cholesterol, and lowering the small dense fraction of low-density lipoprotein (LDL) cholesterol. Their efficacy for secondary prevention of serious vascular events is unclear, and to date no systematic review focusing on secondary prevention has been undertaken. OBJECTIVES: To assess the efficacy and safety of fibrates for the prevention of serious vascular events in people with previous cardiovascular disease (CVD), including coronary heart disease and stroke. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 9, 2014) on the Cochrane Library, MEDLINE (OVID, 1946 to October week 1 2014), EMBASE (OVID, 1980 to 2014 week 41), the China Biological Medicine Database (CBM) (1978 to 2014), the Chinese National Knowledge Infrastructure (CNKI) (1979 to 2014), Chinese Science and Technique Journals Database (VIP) (1989 to 2014). We also searched other resources, such as ongoing trials registers and databases of conference abstracts, to identify further published, unpublished, and ongoing studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in which a fibrate (for example gemfibrozil, fenofibrate) was compared with placebo or no treatment. We excluded RCTs with only laboratory outcomes. We also excluded trials comparing two different fibrates without a placebo or no-treatment control. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed risk of bias, and extracted the data. We contacted authors of trials for missing data. MAIN RESULTS: We included 13 trials involving a total of 16,112 participants. Eleven trials recruited participants with history of coronary heart disease, two trials recruited participants with history of stroke, and one trial recruited participants with a mix of people with CVD. We judged overall risk of bias to be moderate. The meta-analysis (including all fibrate trials) showed evidence for a protective effect of fibrates primarily compared to placebo for the primary composite outcome of non-fatal stroke, non-fatal myocardial infarction (MI), and vascular death (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.83 to 0.94; participants = 16,064; studies = 12; I(2) = 45%, fixed effect). Fibrates were moderately effective for preventing MI occurrence (RR 0.86, 95% CI 0.80 to 0.93; participants = 13,942; studies = 10; I(2) = 24%, fixed effect). Fibrates were not effective against all-cause mortality (RR 0.98, 95% CI 0.91 to 1.06; participants = 13,653; studies = 10; I(2) = 23%), death from vascular causes (RR 0.95, 95% CI 0.86 to 1.05; participants = 13,653; studies = 10; I(2) = 11%, fixed effect), and stroke events (RR 1.03, 95% CI 0.91 to 1.16; participants = 11,719; studies = 6; I(2) = 11%, fixed effect). Excluding clofibrate trials, as the use of clofibrate was discontinued in 2012 due to safety concerns, the remaining class of fibrates were no longer effective in preventing the primary composite outcome (RR 0.90, 95% CI 0.79 to 1.03; participants = 10,320; studies = 7; I(2) = 50%, random effects). However, without clofibrate data, fibrates remained effective in preventing MI (RR 0.85, 95% CI 0.76 to 0.94; participants = 8304; studies = 6; I(2) = 47%, fixed effect). There was no increase in adverse events with fibrates compared to control. Subgroup analyses showed the benefit of fibrates on the primary composite outcome to be consistent irrespective of age, gender, and diabetes mellitus. AUTHORS' CONCLUSIONS: Moderate evidence showed that the fibrate class can be effective in the secondary prevention of composite outcome of non-fatal stroke, non-fatal MI, and vascular death. However, this beneficial effect relies on the inclusion of clofibrate data, a drug that was discontinued in 2002 due to its unacceptably large adverse effects. Further trials of the use of fibrates in populations with previous stroke and also against a background treatment with statins (standard of care) are required.

Topical clofibrate improves symptoms in patients with atopic dermatitis and reduces serum TARC levels: a randomized, double-blind, placebo-controlled pilot study.

BACKGROUND: Though topical corticosteroids (TC) are used for treating atopic dermatitis (AD) as a standard, there exist several problems including topical steroid addiction (TSA) or Red skin syndrome. Moreover, the number of patients, who refrain from using TC because of steroid-phobia, is increasing. Recently, topical PPAR alpha ligand application has been reported to improve experimental allergic dermatitis. The purpose of this study was to investigate the short-term efficacy and safety of topical clofibrate, one of PPAR alpha ligand, in such steroid-phobic patients with AD. METHODS: This study was conducted as a double-blind design to investigate the effects of random administration of topical clofibrate and base (placebo) on skin manifestation and blood parameters of patients for 2 weeks. Severity was digitized using severity scoring systems for atopic dermatitis by the Japanese Dermatological Association (SSS-JDA) before and after two weeks. Subjective severity of patients was evaluated using visual analog scale (Pt-VAS). Serum thymus and activation-regulated chemokine (TARC) and immunoglobulin E (IgE) were also investigated. RESULTS: Twenty patients were enrolled, and 19 of 20 patients completed the study. In 19 patients, the value of severity score using SSS-JDA was decreased significantly after administration of topical clofibrate (P=0.001). Subjective evaluation using Pt-VAS (P=0.008) and serum TARC levels (P=0.03) were also significantly decreased after two weeks of topical clofibrate. There was not a significant difference in serum IgE levels. No adverse effect was observed. CONCLUSIONS: Topical clofibrate is useful for patients with AD especially who are reluctant to use topical steroids.

Comprehensive analysis reveals key genes and environmental toxin exposures underlying treatment response in ulcerative colitis based on in-silico analysis and Mendelian randomization.

BACKGROUND: UC is increasingly prevalent worldwide and represents a significant global disease burden. Although medical therapeutics are employed, they often fall short of being optimal, leaving patients struggling with treatment non-responsiveness and many related complications. MATERIALS AND METHODS: The study utilized gene microarray data and clinical information from GEO. Gene enrichment and differential expression analyses were conducted using Metascape and Limma, respectively. Lasso Regression Algorithm was constructed using glmnet and heat maps were generated using pheatmap. ROC curves were used to assess diagnostic parameter capability, while XSum was employed to screen for small-molecule drugs exacerbating UC. Molecular docking was carried out using Autodock Vina. The study also performed Mendelian randomization analysis based on TwoSampleMR and used CTD to investigate the relationship between exposure to environmental chemical toxicants and UC therapy responsiveness. RESULTS: Six genes (ELL2, DAPP1, SAMD9L, CD38, IGSF6, and LYN) were found to be significantly overexpressed in UC patient samples that did not respond to multiple therapies. Lasso analysis identified ELL2 and DAPP1 as key genes influencing UC treatment response. Both genes accurately predicted intestinal inflammation in UC and impacted the immunological infiltration status. Clofibrate showed therapeutic potential for UC by binding to ELL2 and DAPP1 proteins. The study also reviews environmental toxins and drug exposures that could impact UC progression. CONCLUSIONS: We used microarray technology to identify DAPP1 and ELL2 as key genes that impact UC treatment response and inflammatory progression. Clofibrate was identified as a promising UC treatment. Our review also highlights the impact of environmental toxins on UC treatment response, providing valuable insights for personalized clinical management.

Clofibrate in combination with phototherapy for unconjugated neonatal hyperbilirubinaemia.

BACKGROUND: There are many pathological conditions leading to an elevated unconjugated bilirubin level (hyperbilirubinaemia) in neonates. Currently the standard therapies for unconjugated hyperbilirubinaemia include phototherapy and exchange transfusion. In addition to phototherapy, clofibrate has been studied as a treatment for hyperbilirubinaemia in several countries. OBJECTIVES: To determine the efficacy and safety of clofibrate in combination with phototherapy versus phototherapy alone in unconjugated neonatal hyperbilirubinaemia. SEARCH METHODS: Randomised controlled trials were identified by searching MEDLINE (1950 to April 2012) before being translated for use in The Cochrane Library, EMBASE 1980 to April 2012 and CINAHL databases. All searches were re-run on 2 April 2012. SELECTION CRITERIA: We included trials where neonates with hyperbilirubinaemia received either clofibrate in combination with phototherapy or phototherapy alone or placebo in combination with phototherapy. DATA COLLECTION AND ANALYSIS: Data were extracted and analysed independently by two review authors (MG and HM). Treatment effects on the following outcomes were determined: mean change in bilirubin levels, mean duration of treatment with phototherapy, number of exchange transfusions needed, adverse effects of clofibrate, bilirubin encephalopathy and neonatal mortality. Study authors were contacted for additional information. Studies were analysed for methodological quality in a 'Risk of bias' table. MAIN RESULTS: Fifteen studies (two including preterm neonates and 13 including term neonates) were included in this review. All but one of the included studies were conducted in Iran. For preterm neonates, there was a significantly lower bilirubin level in the 100 mg/kg clofibrate group compared to the control group with a mean difference of -1.37 mg/dL (95% CI -2.19 mg/dL to -0.55 mg/dL) (-23 µmol/L; 95% CI -36 µmol/L to -9 µmol/L) after 48 hours. For the term neonates, there were significantly lower bilirubin levels in the clofibrate group compared to the control group after both 24 and 48 hours of treatment with a weighted mean difference of -2.14 mg/dL (95% CI -2.53 mg/dL to -1.75 mg/dL) (-37 µmol/L; 95% CI -43 µmol/L to -30 µmol/L] and -1.82 mg/dL (95% CI -2.25 mg/dL to -1.38 mg/dL) (-31 µmol/L; 95% CI -38 µmol/L to -24 µmol/L), respectively.There was a significantly lower duration of phototherapy in the clofibrate group compared to the control group for both preterm and term neonates with a weighted mean difference of -23.82 hours (95% CI -30.46 hours to -17.18 hours) and -25.40 hours (95% CI -28.94 hours to -21.86 hours), respectively.None of the studies reported on bilirubin encephalopathy rates, neonatal mortality rates, or the levels of parental or staff satisfactions with the interventions. AUTHORS' CONCLUSIONS: There are insufficient data from different countries on the use of clofibrate in combination with phototherapy for hyperbilirubinaemia to make recommendations for practice. There is a need for larger trials to determine how effective clofibrate is in reducing the need for, and duration of, phototherapy in term and preterm infants with hyperbilirubinaemia.

Effects of clofibrate on salt loading-induced hypertension in rats.

The effects of clofibrate on the hemodynamic and renal manifestations of increased saline intake were analyzed. Four groups of male Wistar rats were treated for five weeks: control, clofibrate (240 mg/kg/day), salt (2% via drinking water), and salt + clofibrate. Body weight, systolic blood pressure (SBP), and heart rate (HR) were recorded weekly. Finally, SBP, HR, and morphologic, metabolic, plasma, and renal variables were measured. Salt increased SBP, HR, urinary isoprostanes, NOx, ET, vasopressin and proteinuria and reduced plasma free T(4) (FT(4)) and tissue FT(4) and FT(3) versus control rats. Clofibrate prevented the increase in SBP produced by salt administration, reduced the sodium balance, and further reduced plasma and tissue thyroid hormone levels. However, clofibrate did not modify the relative cardiac mass, NOx, urinary ET, and vasopressin of saline-loaded rats. In conclusion, chronic clofibrate administration prevented the blood pressure elevation of salt-loaded rats by decreasing sodium balance and reducing thyroid hormone levels.

Peroxisome proliferator-activated receptor {alpha} agonism prevents renal damage and the oxidative stress and inflammatory processes affecting the brains of stroke-prone rats.

A growing body of evidence suggests that chronic kidney disease is a significant risk for cardiovascular events and stroke regardless of traditional risk factors. The aim of this study was to examine the effects of peroxisome proliferator-activated receptor (PPAR) agonists on the tissue damage affecting salt-loaded spontaneously hypertensive stroke-prone rats ( SHRSPs), an animal model that develops a complex pathology characterized by systemic inflammation, hypertension, and proteinuria and leads to end-organ injury (initially renal and subsequently cerebral). Compared with the PPARγ agonist rosiglitazone, the PPARα ligands fenofibrate and clofibrate significantly increased survival (p < 0.001) by delaying the occurrence of brain lesions monitored by magnetic resonance imaging (p < 0.001) and delaying increased proteinuria (p < 0.001). Fenofibrate completely prevented the renal disorder characterized by severe vascular lesions, tubular damage, and glomerular sclerosis, reduced the number of ED-1-positive cells and collagen accumulation, and decreased the renal expression of interleukin-1ß, transforming growth factor ß, and monocyte chemoattractant protein 1. It also prevented the plasma and urine accumulation of acute-phase and oxidized proteins, suggesting that the protection induced by PPARα agonists was at least partially caused by their anti-inflammatory and antioxidative properties. The results of this study demonstrate that PPAR agonism has beneficial effects on spontaneous brain and renal damage in SHRSPs by inhibiting systemic inflammation and oxidative stress, and they support carrying out future studies aimed at evaluating the effect of PPARα agonists on proteinuria and clinical outcomes in hypertensive patients with renal disease at increased risk of stroke.

Bounds on causal effects in randomized trials with noncompliance under monotonicity assumptions about covariates.

In randomized trials with nonrandom noncompliance, the causal effects of a treatment among the entire population cannot be estimated in an unbiased manner. Therefore, several authors have considered the bounds on the causal effects. Here, we propose bounds by applying an idea of VanderWeele (Biometrics 2008; 64:702-706), who showed that the sign of the unmeasured confounding bias can be determined under monotonicity assumptions about covariates in the framework of observational studies. In randomized trials with noncompliance by switching the treatment, we show that the lower or upper bound on the expectation of the potential outcome becomes the expectation from the per-protocol analysis under monotonicity assumptions similar to those of VanderWeele. In particular, the monotonicity assumptions can yield both the lower and the upper bounds on causal effects when the monotonic relationship between the covariates and the treatment actually received depends on the treatment assigned. The results are extended to cases of noncompliance by subjects not receiving any treatment. Although the monotonicity assumptions are not themselves identifiable, they are nonetheless reasonable in some situations.

The effect of clofibrate with phototherapy in late pre-term newborns with non-hemolytic jaundice.

BACKGROUND: Despite an understanding of the enzymatic pathways leading to bilirubin production and degradation, very few pharmacologic interventions are utilized and the mainstay of treatment remains phototherapy. AIMS: To evaluate the efficacy of clofibrate in reducing total serum bilirubin levels in late pre-term neonates with non-hemolytic jaundice. DESIGN AND SETTING: Double-blind, placebo-controlled, randomized trial; tertiary level neonatal unit. MATERIALS AND METHODS: A randomized controlled study was carried out in the neonatal ward of Children's Hospital, Tabriz, Iran, over a 1-year period. Sixty-eight healthy late pre-term infants readmitted with non-hemolytic hyperbilirubinemia were randomized to receive phototherapy and clofibrate (n= 35) or phototherapy and placebo (n= 33). STATISTICAL ANALYSIS USED: Chi-square test and independent sample 't' test. RESULTS: There were no significant differences in the weight, gender, modes of delivery and age of neonates between the two groups. Similarly the mean total serum bilirubin (TSB) level at the time of admission was not significantly different between the two groups [mean+/- SD: 19.72 +/- 1.79 (95% confidence interval: 19.12-20.54 mg/dL) vs. 20.05 +/- 2.82 (95% confidence interval, 19.54-22.04 mg/dL), P= 0.57]. The mean TSB 48 hours after phototherapy [mean+/- SD: 8.06+/- 1.34 (95% confidence interval: 7.94-10.18 mg/dL) vs.10.94 +/- 2.87 (95% confidence interval: 9.92-12.16 mg/dL), P= 0.02] and the mean duration of phototherapy [mean+/- SD: 64.32 +/- 12.48 (95% confidence interval: 60-81.6 hours) vs. 87.84 +/- 29.76 (95% confidence interval: 79.2-108 hours), P< 0.001] were significantly lower in the clofibrate-treated group. CONCLUSIONS: Clofibrate is an effective adjunctive drug in neonatal hyperbilirubinemia, which results in decreased TSB level and reduced duration of phototherapy in late pre-term newborns.

Efficacy of clofibrate on severe neonatal jaundice associated with glucose-6-phosphate dehydrogenase deficiency (a randomized clinical trial).

Glucose-6-phosphate dehydrogenase (G6PD) deficiency may cause severe hyperbilirubinemia with bilirubin encephalopathy unless intervention is initiated. The aim of this study was to assess the efficacy of clofibrate in full term G6PD deficient neonates with jaundice. A randomized clinical trial study was performed in two groups of full-term G6PD deficient jaundiced neonates (clofibrate treated group, n = 21; control group, n = 19). Infants in the clofibrate group received a single oral dose of 100 mg/kg clofibrate, whereas control group received nothing. Both groups were treated with phototherapy. Serum total and direct bilirubin levels were measured at the onset of treatments, 16, 24 and 48 hours later. On enrollment, the mean total serum bilirubin (TSB) level in the clofibrate treated group was 18.40 +/- 2.41 and in the control group was 17.49 +/- 1.03 (p = 0.401). At 16, 24 and 48 hours of treatment, the mean TSB in the clofibrate group were 15.2 +/- 1.9, 12.6 +/- 2.4, and 10.1 +/- 2.4 and in the control group were 16.5 +/- 1.2, 13.3 +/- 2.2 and 11.4 +/- 2.4, respectively (p = 0.047). At 48 hours, 7 (33%) cases in the clofibrate group and one (5%) case in the control group were discharged with a TSB < 10 mg/dl (p = 0.031). No side effects were observed on serial examinations during hospitalization, or on the 1st and 7th days after discharge. The results show that clofibrate induces a faster decline in serum total bilirubin level, a shorter duration of phototherapy, and hospitalization with no side effects in full-term G6PD deficient neonates with jaundice.

Metabolic relationships among the plasma lipoproteins. Reciprocal changes in the concentrations of very low and low density lipoproteins in man.

The changes in other plasma lipoproteins which accompany alterations in very low density lipoproteins (VLDL) were studied in 31 normal and hyperlipidemic men and women who underwent weight reduction, carbohydrate induction, or clofibrate treatment. Plasma lipids and individual lipoprotein cholesterol concentrations were measured serially during control and treatment periods. Low density lipoprotein (LDL) protein was determined by radial immunodiffusion. Oppositely directed changes in VLDL and LDL were found with each of the three metabolic perturbations. Changes in high density lipoprotein (HDL) cholesterol generally paralleled those in LDL but were less consistent. Two patients with type III hyperlipoproteinemia failed to demonstrate reciprocal increases in LDL despite more than 40% reduction in plasma glycerides or VLDL with weight reduction or clofibrate therapy. After clofibrate therapy, LDL increased in proportion to the absolute decrease in VLDL cholesterol during treatment. LDL protein changed relatively less than did LDL cholesterol. The mechanism for the interdependency of plasma VLDL and LDL concentrations over the long term is not known and may be the result of altered rates of interconversion of these lipoproteins, or to feedback inhibition by VLDL of LDL production and release.

Effect of clofibrate in jaundiced full-term infants:a randomized clinical trial.

BACKGROUND: Hyperbilirubinemia is a common problem in newborn infants. It can progress to kernicterus in severe forms, unless an intervention is initiated. The objective of this study was to determine the therapeutic effect of clofibrate in full-term neonates with nonhemolytic jaundice. METHODS: A randomized clinical trial was performed on two groups of full-term jaundiced neonates: the clofibrate-treated group (n = 30) and the control group (n = 30). Infants in the clofibrate group received a single oral dose of 100 mg/kg clofibrate while the neonates in the control group received distilled water (same color and volume); both groups received phototherapy. Serum total and direct bilirubin levels were measured at the beginning, 16, 24, 48, and 74 hours, after the start of the trial. RESULTS: The mean+/-SD total serum bilirubin level of the control and clofibrate groups at enrollment was 17.5+/-2.3 and 18.2+/-1.9 mg/dL, respectively (P = 0.199). The mean+/-SD total serum bilirubin in the control and clofibrate groups after 48 hours was 11.4+/-2.4 and 10.1+/-2.4 mg/dL, respectively (P = 0.047). After 72 hours of intervention, 25 (83%) neonates of the clofibrate group and 16 (53%) of the control group were discharged with a total serum bilirubin of <10 mg/dL (P = 0.026). No side-effect was observed on serial examination during hospitalization, and on the first and seventh day after discharge. CONCLUSION: Clofibrate results in a faster decline in TSB, shorter duration of hospitalization and had no side effects in jaundiced full-term neonates.

Clofibrate as an Adjunct to Phototherapy for Unconjugated Hyperbilirubinemia in Term Neonates.

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.

Protective effect of simvastatin and VULM 1457 in ischaemic-reperfused myocardium of the diabetic-hypercholesterolemic rats.

This study examined the effects of simvastatin (10 mg/ kg) and VULM 1457 (50 mg/kg), an ACAT inhibitor, in the heart model of 6 min ischemia followed by 10 min reperfusion injury in the diabetic-hypercholesterolaemic (DM-HCH) rats. In the DM-HCH rats, the incidence of ventricular tachycardia (VT) had a tendency to be increased, while ventricular fibrillation (VF) occurred in all diseased rats (p < 0.01). Simvastatin and VULM 1457 with the shown hypolipidemic effect, significantly (p < 0.01) suppressed a formation of VF (38% and 29%; respectively).

Up-regulation of Hnf1α gene expression in the liver of rats with experimentally induced chronic renal failure - A possible link between circulating PCSK9 and triacylglycerol concentrations.

BACKGROUND: The aim of this study was to verify if an increase in Hnf1α gene expression could be a possible link between circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) and TAGs concentrations in chronic renal failure (CRF). METHODS: Rats underwent 5/6 nephrectomy or a sham surgery. Liver expressions of Pcsk9, Mttp, ApoB-100, Hnf1α, Hnf4α, lipogenic enzymes and ß-actin genes were quantified by qPCR. Liver levels of proteins coding by these genes were analyzed by Western blotting. Serum apoB-100 and PCSK9 concentration were estimated with an immunoassay. RESULTS: CRF rats showed an increase in circulating concentrations of TAGs, VLDL, apoB-100 and PCSK9, along with an enhanced liver VLDL-TAG secretion rate and a coordinated liver up-regulation of genes coding: a) lipogenic enzymes; b) Mttp and ApoB-100; c) Pcsk9; d) Hnf1α and Hnf4α. Positive correlations were found between serum creatinine concentrations and: a) the liver levels of HNF1α mRNA (r = 0.79, p < 0.01) and HNF4α (r = 0.76, p < 0.01); b) the liver levels of PCSK9 mRNA (r = 0.88, p < 0.01) and serum PCSK9 concentrations (r = 0.73, p < 0.01); c) the liver levels of apoB-100 mRNA (r = 0.83, p < 0.01) and serum apoB-100 concentrations (r = 0.87, p < 0.01). Clofibrate treatment was shown to concomitantly decrease the liver levels of HNF1α, HNF4α and PCSK9 mRNA, as well as serum PCSK9, TAGs and total cholesterol concentrations in CRF rats. CONCLUSION: The results presented are consistent with a cause-effect relationship between the enhanced liver expression of Hnf1α gene and its target genes the products of which are involved in synthesis, assembly and secretion of VLDL, as well as Pcsk9 gene in CRF rats. This may at least in part explain an association between circulating PCSK9 and TAGs in CRF rats and possibly also in humans with chronic kidney disease (CKD).

Modulation of fatty acid metabolism by glucagon in man. III. Role of pharmacologic limitation of FFA availability.

This study was undertaken to examine the contribution of plasma free fatty acid availability upon the regulation of ketone body and endogenous triglyceride concentration in man. This substrate-product relationship was examined both in the basal state and during hormonally induced ketogenic stimulation. Five insulin-deficient diabetics receiving a fixed dose of exogenous insulin were studied after a twelve-hour fast and twenty-four hours after their last therapeutic insulin injection. Reduction in basal free fatty acid concentration was induced with two weeks of clofibrate administration, and hormonal ketogenic stimulation was induced with glucagon administration. A highly significant correlation was observed between the basal free fatty acid level and the basal ketone body concentration. This substrate-product relationship persisted throughout hormonally induced ketogenic stimulation, suggesting that the basal free fatty acid concentration is a major determinant of the plasma ketone body concentration in man. In contrast, alterations in basal free fatty acid concentration were not accompanied by consistent changes in plasma triglyceride concentration, suggesting that plasma free fatty acid concentration may not be the principal determinant of the endogenous triglyceride concentration in clofibrate-treated diabetic man.

Potentiation of hypoglycemic effect of chlorpropamide and phenfromin by halofenate.

The potentiation of oral hypoglycemic drugs by the antilipemic agent halofenate is reported. Forty-seven diabetic patients were treated for 48 weeks with halofenate, clofibrate, or placebo. Five patients in the halofenate group were taking phenformin plus either chlorpropamide or tolbutamide. Their average initial fasting plasma glucose was 160 mg./dl. All five patients experienced a slow but but substantial fall in fasting plasma glucose. The mean fasting plasma glucose for the five patients after 80 days of halofenate treatment was 63 mg./dl. As oral treatment for diabetes was reduced, the fasting plasma glucose returned to prehalofenate levels. In this study, we did ont detect an effect of halofenate on the fasting plasma glucose of diabetic patients treated with insulin or on the fasting plasma glucose levels of patients treated with diet alone.

Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin.

The Coronary Drug Project was conducted between 1966 and 1975 to assess the long-term efficacy and safety of five lipid-influencing drugs in 8,341 men aged 30 to 64 years with electrocardiogram-documented previous myocardial infarction. The two estrogen regimens and dextrothyroxine were discontinued early because of adverse effects. No evidence of efficacy was found for the clofibrate treatment. Niacin treatment showed modest benefit in decreasing definite nonfatal recurrent myocardial infarction but did not decrease total mortality. With a mean follow-up of 15 years, nearly 9 years after termination of the trial, mortality from all causes in each of the drug groups, except for niacin, was similar to that in the placebo group. Mortality in the niacin group was 11% lower than in the placebo group (52.0 versus 58.2%; p = 0.0004). This late benefit of niacin, occurring after discontinuation of the drug, may be a result of a translation into a mortality benefit over subsequent years of the early favorable effect of niacin in decreasing nonfatal reinfarction or a result of the cholesterol-lowering effect of niacin, or both.

Drug interactions with fibric acids.

Fibric acid derivatives may interact with other drugs and the interactions can be of clinical relevance. The pharmacological properties and effects of these drugs which pertain to their potential for drug interactions, are: (a) a very high binding affinity to plasma proteins, especially albumin; (b) the changes produced in vitamin K kinetics; (c) endoplasmic reticulum hyperplasia; (d) induction of cytochrome P450; (e) changes in xenobiotic-metabolizing enzymes; (f) their capability to have a direct effect on carbohydrate metabolism and/or regulation; and (g) potential pharmacokinetic interactions with antidiabetic drugs. Other types of interactions may affect the safety and/or the therapeutic efficacy of fibrates. These interactions are not necessarily risky, but may be important in the long term. Other clinically relevant interactions with less commonly used drugs have been described. Fibrates will continue to be used because they have proved to be safe and effective in correcting many types of dyslipidemia by reducing serum levels of total cholesterol and triglycerides and by increasing high density lipoprotein cholesterol. Furthermore, they have been proven to decrease morbidity and morality from coronary heart disease. Therefore, awareness of their potential drug interactions is most relevant to their safe clinical therapeutic use.