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Aim: Up to 40% of patients with primary biliary cholangitis (PBC) will have a suboptimal biochemical response to ursodeoxycholic acid (UDCA), which can be improved by the addition of fibrates. This exploratory study aims to evaluate the long-term real-life biochemical response of different fibrates, including ciprofibrate, in subjects with UDCA-unresponsive PBC.Methods: The Brazilian Cholestasis Study Group multicenter database was reviewed to assess the response rates to UDCA plus fibrates in patients with UDCA-unresponsive PBC 1 and 2 years after treatment initiation by different validated criteria.Results: In total, 27 patients (100% women, mean age 48.9 ± 9.2 years) with PBC were included. Overall response rates to fibrates by each validated criterion varied from 39 to 60% and 39–76% at 12 and 24 months after treatment combination, respectively. Combination therapy resulted in a significant decrease in ALT and ALP only after 2 years, while GGT significantly improved in the first year of treatment. Treatment response rates at 1 and 2 years appear to be comparable between ciprofibrate and bezafibrate using all available criteria.Conclusion: Our findings endorse the efficacy of fibrate add-on treatment in PBC patients with suboptimal response to UDCA. Ciprofibrate appears to be at least as effective as bezafibrate and should be assessed in large clinical trials as a possibly new, cheaper, and promising option for treatment of UDCA-unresponsive PBC patients.

Aim: Up to 40% of patients with primary biliary cholangitis (PBC) will have a suboptimal biochemical response to ursodeoxycholic acid (UDCA), which can be improved by the addition of fibrates. This exploratory study aims to evaluate the long-term real-life biochemical response of different fibrates, including ciprofibrate, in subjects with UDCA-unresponsive PBC. Methods: The Brazilian Cholestasis Study Group multicenter database was reviewed to assess the response rates to UDCA plus fibrates in patients with UDCA-unresponsive PBC 1 and 2 years after treatment initiation by different validated criteria. Results: In total, 27 patients (100% women, mean age 48.9 ± 9.2 years) with PBC were included. Overall response rates to fibrates by each validated criterion varied from 39 to 60% and 39–76% at 12 and 24 months after treatment combination, respectively. Combination therapy resulted in a significant decrease in ALT and ALP only after 2 years, while GGT significantly improved in the first year of treatment. Treatment response rates at 1 and 2 years appear to be comparable between ciprofibrate and bezafibrate using all available criteria. Conclusion: Our findings endorse the efficacy of fibrate add-on treatment in PBC patients with suboptimal response to UDCA. Ciprofibrate appears to be at least as effective as bezafibrate and should be assessed in large clinical trials as a possibly new, cheaper, and promising option for treatment of UDCA-unresponsive PBC patients. [ABSTRACT FROM AUTHOR]

Introduction and objectives: Little is known about primary biliary cholangitis (PBC) in non-whites. The purpose of this study was to evaluate clinical features and outcomes of PBC in a highly admixed population. Material and methods: The Brazilian Cholestasis Study Group multicentre database was reviewed to assess demographics, clinical features and treatment outcomes of Brazilian patients with PBC. Results: 562 patients (95% females, mean age 51 § 11 years) with PBC were included. Concurrent autoimmune diseases and overlap with autoimmune hepatitis (AIH) occurred, respectively, in 18.9% and 14%. After a mean follow-up was 6.2 § 5.3 years, 32% had cirrhosis, 7% underwent liver transplantation and 3% died of liver-related causes. 96% were treated with ursodeoxycholic acid (UDCA) and 12% required add-on therapy with fibrates, either bezafibrate, fenofibrate or ciprofibrate. Response to UDCA and to UDCA/fibrates therapy varied from 39%-67% and 42-61%, respectively, according to different validated criteria. Advanced histological stages and non-adherence to treatment were associated with primary non-response to UDCA, while lower baseline alkaline phosphatase (ALP) and aspartate aminotransferase (AST) levels correlated with better responses to both UDCA and UDCA/fibrates. Conclusions: Clinical features of PBC in highly admixed Brazilians were similar to those reported in Caucasians and Asians, but with inferior rates of overlap syndrome with AIH. Response to UDCA was lower than expected and inversely associated with histological stage and baseline AST and ALP levels. Most of patients benefited from add-on fibrates, including ciprofibrate. A huge heterogeneity in response to UDCA therapy according to available international criteria was observed and reinforces the need of global standardization. [ABSTRACT FROM AUTHOR]

A continuous flow procedure for the gem-dichlorocyclopropanation of alkenes has been developed. The method is based on the generation of dichlorocarbene utilizing the classical biphasic aqueous sodium hydroxide/chloroform system. This reaction typically requires vigorous stirring for several hours in batch for completion. Tarry materials precipitate due to partial polymerization of dichlorocarbene and the process is difficult to scale. To overcome these problems and achieve very efficient mixing during the flow process a column reactor packed with PTFE beads as inert filling material has been used. PTFE beads have been found to be the optimal material to obtain fine dispersions of the aqueous phase in the organic solution. By heating the packed-bed reactor at 80 °C excellent conversions have been achieved after a residence time of only 4 min. The process has been applied for the synthesis of Ciprofibrate, a dichlorocyclopropane-containing drug used as treatment for several diseases associated with high lipid content in blood. [ABSTRACT FROM AUTHOR]

A novel stability-indicating high-performance liquid chromatographic assay method was developed and validated for quantitative determination of ciprofibrate in bulk drugs and in pharmaceutical dosage form in the presence of degradation products. An isocratic, reversed phase HPLC method was developed to separate the drug from the degradation products, using an Ace5-C18 (250×4.6 mm, 5 μm) advance chromatography column, and methanol and water (90:10 v/v) as a mobile phase. The detection was carried out at a wavelength of 232 nm. The ciprofibrate was subjected to stress conditions of hydrolysis (acid, base), oxidation, photolysis and thermal degradation. Degradation was observed for ciprofibrate in base, in acid and in 30% H2O2. The drug was found to be stable in the other stress conditions attempted. The degradation products were well resolved from the main peak. The percentage recovery of ciprofibrate was from (98.65 to 100.01%) in the pharmaceutical dosage form. The developed method was validated with respect to linearity, accuracy (recovery), precision, system suitability, specificity and robustness. The forced degradation studies prove the stability indicating power of the method.

Ciprofibrate is a drug indicated in cases of hypertriglyceridemia and mixed hyperlipidemia, but no monographs are available in official compendia for the analysis of this substance in tablets. The objective of this work was to develop and validate a spectrophotometric method for routine analysis of ciprofibrate in tablets. In this study, commercial and standard ciprofibrate were used, as well as placebo in absolute ethanol, analyzed by UV spectrophotometer. All tests followed the rules of Resolution RE-899, 2003. The results showed that the developed and validated method offers low cost, easy implementation, precision and accuracy, and may be included in the routine of quality control laboratories.O ciprofibrato é um fármaco indicado em casos de hipertrigliceridemia e hiperlipidemia mista, mas não há monografias em compêndios oficiais para a análise desta substância em comprimidos. O objetivo deste trabalho é desenvolver e validar um método espectrofotométrico para análise de rotina de ciprofibrato em comprimidos. Neste estudo foram empregados ciprofibrato comercial, padrão e placebo em etanol absoluto, analisadas por espectrofotometria UV. Todos os testes seguiram as regras da Resolução RE- 899, 2003. Os resultados mostraram que o método desenvolvido e validado apresenta baixo custo, fácil implementação, precisão e exatidão e pode ser incluído em rotina de laboratórios de controle de qualidade.

Association between hypertriglyceridemia and cardiovascular (CV) disease is still controversial. The purpose of this study was to compare omega-3 and ciprofibrate effects on the vascular structure and function in low and high CV risk hypertensive patients with hypertriglyceridemia. Twenty-nine adults with triglycerides 150–499 mg/dL were divided into low (<7.5%) and high (≥7.5%) CV risk, randomized to receive omega-3 fatty acids 1800 mg/d or ciprofibrate 100 mg/d for 12 weeks. Treatment was switched after 8-week washout. Clinical evaluation and vascular tests were assessed at baseline and after intervention. Peripheral (131 ± 3 to 125 ± 3 mm Hg, P < .05) and aortic (124 ± 3 to 118 ± 2 mg/dL, P < .05) systolic blood pressure were decreased by ciprofibrate in low-risk patients. In high-risk patients, pulse wave velocity was reduced (10.4 ± 0.4 to 9.4 ± 0.3 m/s, P < .05) and flow-mediated dilation was increased (11.1 ± 1.6 to 13.5 ± 1.2%, P < .05) by omega-3. In conclusion, omega-3 improved arterial stiffness and endothelial function, pointing out the beneficial effect of this therapy on vascular aging, in high-risk patients. [ABSTRACT FROM AUTHOR]

Aim. To compare efficacy of simvastatin, a II generation statin, and ciprofibrate, a III generation fibrate, in various types of hyperlipidemia (HLP) and fibrate pharmacokinetic variants. Material and methods. The authors examined 156 males with primary HLP, aged 41-59. Inclusion criteria were: initial cholesterol (CH) >190 mg/dl; triglycerides (TG) >150 mg/dl; high-density lipoprotein CH >35 mg/dl. Clinical, biochemical, pharmacokinetic, and statistical methods were used. Results. Analysis of lipid-transport system in patients with isolated hypertriglyceridemia (HTG) during 8-week ciprofibrate therapy demonstrated decreases in TG (by 39.2%; pIII-V

Aim. To investigate hypolipidemic and antioxidant effects of probucol and ciprofibrate, their influence of blood rheology and clinical course of angina pectoris, during monotherapy and combined therapy, as a part of coronary heart disease (CHD) complex management. Material and methods. The study included 112 CHD patients, who were administered probucol (n=39), ciprofibrate (n=37), or their combination (n=36) for 3 months. Before the treatment, all participants were administered placebo for one month. The authors used clinical, instrumental (angina episodes frequency assessment, veloergometry), and biochemical methods (measuring levels of lipid fractions, lipid peroxidation (LP) products, antioxidant enzymes, fibrinogen and antithrombin III, as well as red blood cell and platelet aggregation). Results. Combined with standard antianginal therapy in CHD patients, probucol substantially decreased LP product levels, activated glutathione peroxidase and superoxide dismutase, inhibited red blood cell and platelet aggregation. Ciprofibrate improved lipid profile, decreased fibrinogen level, and increased antithrombin III level. Combined therapy by probucol and ciprofibrate demonstrated greater hypolipidemic, antioxidant, hemorheological, and clinical effects than monotherapy. Conclusion. Probucol and ciprofibrate can be used as monotherapy and in combination for CHD complex management, asmedications that have not only hipolipidemic action , but also antioxidant, hemorheological and antianginal effects.

Objective: Ciprofibrate (2-[4-(2,2-dichloro cyclopropyl) phenoxyl]-2-methyl propinoic acid) is a lipid-lowering drug used in the treatment of various metabolic diseases, especially hyperlipidemias. Human carbonic anhydrase II (hCA II) and glucose 6 phosphate dehydrogenase (G6PD) are crucial enzymes associated with many metabolic pathways. The aim of this study was to reveal the in vitro effect of ciprofibrate on the hydratase and esterase activities of hCAII and G6PD enzyme activity. Methods: hCA II hydratase activity was measured using the modified Wilbur-Anderson method, while esterase activity was determined using the method described by Armstrong et al. G6PD activity was determined using the Beutler method. Results: Different concentrations of ciprofibrate increased hCAII hydratase activity but exhibited no effects on hCA II esterase or G6PD activities. Conclusion: Since activation of hCA II is important in neurodegenerative diseases, such as Alzheimer's, in which carbonic anhydrase activity decreases, the use of ciprofibrate may be proposed in the treatment of such diseases. However, this now needs to be confirmed by in vivo studies. [ABSTRACT FROM AUTHOR]

A derivative UV spectrophotometric and a reversed phase high-performance liquid chromatographic method for determination of ciprofibrate in tablets was developed. The first-order derivative UV spectrophotometric method found to be accurate with 100.57±0.97 recovery and precise with a coefficient of variation of 1.44. These results were compared to those obtained by reference methods, zero-order UV spectrophotometric method and a reversed-phase high-performance liquid chromatography method. A reversed-phase C8 column with methanol:water (90:10, pH 3.7) mobile phase was used and the detector wavelength was set at 232 nm. Calibration solutions used in HPLC were ranging from 2 to 12 µg/ml. An ANOVA test (P = 0.0226, F = 4.935) showed that the results obtained with the derivative UV spectrophotometric method were comparable to those obtained using reference methods. [ABSTRACT FROM AUTHOR]

Abstract: A rapid, sensitive and specific method for quantifying ciprofibrate in human plasma using bezafibrate as the internal standard (IS) is described. The sample was acidified prior extraction with formic acid (88%). The analyte and the IS were extracted from plasma by liquid–liquid extraction using an organic solvent (diethyl ether/dichloromethane 70/30 (v/v)). The extracts were analyzed by high performance liquid chromatography coupled with electrospray tandem mass spectrometry (HPLC–MS/MS). Chromatography was performed using Genesis C18 4μm analytical column (4.6×150mm i.d.) and a mobile phase consisting of acetonitrile/water (70/30, v/v) and 1mM acetic acid. The method had a chromatographic run time of 3.4min and a linear calibration curve over the range 0.1–60μg/mL (r >0.99). The limit of quantification was 0.1μg/mL. The intra- and interday accuracy and precision values of the assay were less than 13.5%. The stability tests indicated no significant degradation. The recovery of ciprofibrate was 81.2%, 73.3% and 76.2% for the 0.3, 5.0 and 48.0ng/mL standard concentrations, respectively. For ciprofibrate, the optimized parameters of the declustering potential, collision energy and collision exit potential were −51V, −16eV and −5V, respectively. The method was also validated without the use of the internal standard. This HPLC–MS/MS procedure was used to assess the bioequivalence of two ciprofibrate 100mg tablet formulations in healthy volunteers of both sexes. The following pharmacokinetic parameters were obtained from the ciprofibrate plasma concentration vs. time curves: AUClast, AUC0–168h, C max and T max. The geometric mean with corresponding 90% confidence interval (CI) for test/reference percent ratios were 93.80% (90% CI=88.16–99.79%) for C max, 98.31% (90% CI=94.91–101.83%) for AUClast and 97.67% (90% CI=94.45–101.01%) for AUC0–168h. Since the 90% CI for AUClast, AUC0–168h and C max ratios were within the 80–125% interval proposed by the US FDA, it was concluded that ciprofibrate (Lipless® 100mg tablet) formulation manufactured by Biolab Sanus Farmacêutica Ltda. is bioequivalent to the Oroxadin® (100mg tablet) formulation for both the rate and the extent of absorption. [Copyright &y& Elsevier]

Abstract: It is well known that the hypolipidemic drug ciprofibrate induces peroxisome proliferation in rodent liver, which in turn leads to the oxidative stress, and modifies some parameters related to cell proliferation and apoptosis. The administration of ciprofibrate to rats during the lactating period determined in their pups significant modifications in hepatic peroxisome enzyme activities, induction of the PPARα-target gene, Cyp4a10, and perturbation in cell proliferation and apoptosis, which affected the size of the liver. Moreover, this modification was associated to about two-fold induction of mRNA-PPARα. On the contrary, in the kidney, although a similar two-fold up-regulation of PPARα was detected, the induction of both peroxisomal enzyme activities and Cyp4a10 were weak, and no alterations were detected, neither in cell cycle nor in the size of the tissue. Our results indicate that the response to ciprofibrate is stronger in the liver than in the kidney of newborn rats. [Copyright &y& Elsevier]

Abstract: Peroxisome proliferators (PPs) are a diverse class of chemicals, which cause a dramatic increase in the size and number of hepatic peroxisomes in rodents and eventually lead to the development of hepatic tumors. Nuclear factor-κB (NF-κB) is a transcription factor activated by reactive oxygen and is involved in cell proliferation and apoptosis. Previously we found that the peroxisome proliferator ciprofibrate (CIP) activates NF-κB and that dietary vitamin E decreases CIP-induced NF-κB DNA binding. We, therefore, hypothesized that inhibition of NF-κB by vitamin E is necessary for effects of vitamin E on CIP-induced cell proliferation and the inhibition of apoptosis by CIP. Sixteen B6129 female mice (p50+/+) and twenty mice deficient in the p50 subunit of NF-κB (p50−/−) were fed a purified diet containing 10 or 250mg/kg vitamin E (α-tocopherol acetate) for 28 days. At that time, half of the mice were placed on the same diet with 0.01% CIP for 10 days. CIP treatment increased the DNA binding activity of NF-κB and cell proliferation, but had no significant effect on apoptosis. Compared to wild-type mice, the p50−/− mice had lower NF-κB activation, higher basal levels of cell proliferation and apoptosis, and a lower ratio of reduced glutathione to oxidized glutathione (GSH/GSSG). There was approximately a 60% reduction in cell proliferation in the CIP-treated p50−/− mice fed higher vitamin E in comparison to the p50−/− mice fed lower vitamin E. Dietary vitamin E also inhibited the DNA binding activity of NF-κB, increased apoptosis, and increased the GSH/GSSG ratio. This study shows the effects of vitamin E on cell growth parameters do not appear to be solely through decreased NF-κB activation, suggesting that vitamin E is acting by other molecular mechanisms. [Copyright &y& Elsevier]

Abstract: Testicular and adrenal steroidogenic enzymes were measured radiometrically following oral dosing of rats with ciprofibrate (2-[4-(2,2-dichlorocyclopropyl) phenoxyl]-2-methylpropinoic acid), a peroxisome proliferator. Six-week-old male Fisher 344 rats were fed a diet containing ciprofibrate (0.025%, w/w) for 3, 7, 14, 28, 56, 84, 112 or 140 days leading to a daily ciprofibrate intake of approximately 15mg/kg body weight/day. Ciprofibrate caused a marked inhibition of testicular 3β-hydroxysteroid dehydrogenase-isomerase (3β-HSD) activity that was significant after 3 days and subsequently decreased to 40% of control level. Ciprofibrate treatment also reduced 17β-hydroxysteroid dehydrogenase (17β-HSD) activity to a lesser extent but had no effect on 17-hydroxylase (17-OHase) activity. Immunoblot analyses indicated that ciprofibrate treatment did not alter enzyme protein levels and semi-quantitative RT-PCR analysis also revealed no significant changes in testicular 3β-HSD mRNA levels. Furthermore, in addition to the enzyme-specific effect of ciprofibrate on 3β-HSD in the testes, a tissue-specific effect was also evident, since no significant effects of ciprofibrate were seen on the activities of 3β-HSD or 21-OHase in the adrenal glands from the same animals. [Copyright &y& Elsevier]

Aims Diabetic dyslipidaemia with decreased high-density lipoprotein-cholesterol (HDL-C) concentration plays a key role in enhanced atherosclerosis. The antioxidant effect of HDL is due to the influence of human paraoxonase 1 (PON1) and several authors have described decreased activity of this enzyme in Type 2 diabetics and subjects with metabolic syndrome. The goal of this study was to examine the effect of daily ciprofibrate on serum PON1 and lipoprotein concentrations in patients with metabolic syndrome. Methods Fifty-one patients with metabolic syndrome were enrolled into the study. We examined the effect of 100 mg day−1 ciprofibrate treatment on lipid concentrations, oxidized low-density lipoprotein (LDL), PON1 concentrations and activity. We also investigated the calculated size of LDL-cholesterol (LDL-C). Results During the 3-month study, it was observed that following treatment with ciprofibrate, the serum triglyceride concentration decreased significantly (from 2.76 ± 0.9 mmol l−1 to 2.27 ± 1.6 mmol l−1; −18%; P < 0.001), while HDL-C increased significantly (from 0.95 ± 0.2 mmol l−1 to 1.2 ± 0.3 mmol l−1; 26%; P < 0.001). The oxidatively modified LDL-C concentration decreased significantly (from 137 ± 19 U l−1 to 117 ± 20 U l−1; P < 0.001), while HDL-associated apolipoprotein A1 significantly increased (from 1.35 ± 0.2 g l−1 to 1.75 ± 0.3 g l−1; P < 0.001). The LDL-C/LDL-apoB ratio, which reflects the size of LDL, increased significantly (from 0.96 ± 0.05 to 1.05 ± 0.06; P < 0.05). Serum PON1 activity was significantly elevated (from 108 ± 34 U l−1 to 129 ± 31 U l−1; P < 0.05), while standardized values for HDL-C remained significantly unchanged (PON1/HDL-C) (from 114 ± 21 to 107 ± 20; NS). Conclusion Three months of treatment with ciprofibrate favourably affected the lipid profile, increased LDL resistance to oxidation and improved antioxidant status by increasing serum paraoxonase activity in these patients. [ABSTRACT FROM AUTHOR]

Abstract: Six antihyperlipidemic agents—bezafibrate, ciprofibrate, clofibrate, clofibric acid, fenofibrate and gemfibrozil were separated by means of capillary electrophoresis, using unmodified fused silica tubing of 75  m internal diameter and 87 cm length (65 cm to the UV detector at 227 nm). Migration time and selectivity were examined in differing pH of separation buffer, varying separation voltage and differing temperature. Optimal separation was achieved using 1/15 M phosphate buffer pH 10, 240 V/cm at 25  C. The optimal separation conditions were then used to elaborate the method of quantitation of bezafibrate, ciprofibrate and gemfibrozil in Bezamidin, Lipanor and Gemfibral pharmaceuticals. The clofibric acid was used as internal standard. The calibration curve was constructed from 0.2 to 0.8 mg/ml of each compound and 0.5 mg/ml of internal standard. The calibration data were proved to be linear by Mandel and Lack-of-fit tests. Statistical evaluation of results proved proper recovery of elaborated method (102.42, 97.32 and 101.51%, respectively) and good repeatability (9.51, 5.52 and 11.15%, respectively). The linearity of recovery was also tested by analyzing increasing amount of the samples. Three fortified samples of each drug were also analyzed to perform additional accuracy validation. [Copyright &y& Elsevier]

Multiple methods currently exist for the assessment of peroxisome proliferation, including gene expression, enzyme activity, immunolabeling coupled with image analysis, and electron microscopy. This study describes a novel flow cytometric method to efficiently quantify peroxisome proliferation in cells from frozen livers. Frozen livers from cynomolgus monkeys treated with ciprofibrate at doses of 0, 3, 30, 150, and 400 mg/kg/day for 15 days were mechanically disaggregated using an automated dispersion method. The resulting cell suspensions were labeled using an allophycocyanin (APC)-conjugated antibody directed against peroxisomal membrane protein 70 (PMP70). Statistically significant increases in mean fluorescence intensity were observed from animals dosed at 30, 150, and 400 mg/kg/day compared to control. Parallel comparisons using electron microscopy and immunofluorescence microscopy suggest that flow cytometry may be an alternative to electron microscopy in determinations of peroxisome proliferation. Flow cytometric analysis of freshly isolated hepatocytes and frozen liver from rats treated with fenofibrate at 200 mg/kg/day for 10 days showed the flow cytometric method could detect peroxisome proliferation in both species. The research described here demonstrates the feasibility of applying flow cytometry for the detection of peroxisome proliferation. [ABSTRACT FROM AUTHOR]

Fibrates, such as ciprofibrate, fenofibrate, and clofibrate, are peroxisome proliferator-activated receptor-α (PPARα) agonists that have been in clinical use for many decades for treatment of dyslipidemia. When mice and rats are given PPARα agonists, these drugs cause hepatic peroxisome proliferation, hypertrophy, hyperplasia, and eventually hepatocarcinogenesis. Importantly, primates are relatively refractory to these effects; however, the mechanisms for the species differences are not clearly understood. Cynomolgus monkeys were exposed to ciprofibrate at various dose levels for either 4 or 15 days, and the liver transcriptional profiles were examined using Affymetrix human GeneChips. Strong upregulation of many genes relating to fatty acid metabolism and mitochondrial oxidative phosphorylation was observed; this reflects the known pharmacology and activity of the fibrates. In addition, (1) many genes related to ribosome and proteasome biosynthesis were upregulated, (2) a large number of genes downregulated were in the complement and coagulation cascades, (3) a number of key regulatory genes, including members of the JUN, MYC, and NFκB families were downregulated, which appears to be in contrast to the rodent, where JUN and MYC are reported to upregulated after PPARα agonist treatment, (4) no transcriptional signal for DNA damage or oxidative stress was observed, and (5) transcriptional signals consistent with an anti-proliferative and a pro-apoptotic effect were seen. We also compared the primate data to literature reports of hepatic transcriptional profiling in PPARα-treated rodents, which showed that the magnitude of induction in β-oxidation pathways was substantially greater in the rodent than the primate. [ABSTRACT FROM AUTHOR]

Impairment of flow-mediated dilation (FMD) has been shown to be associated with hypercholesterolemia and hypertriglyceridemia and reduction of cholesterol and/or triglyceride levels can improve FMD. In hyperlipidemia the role of inflammatory substances on endothelial function requires further clarification. In patients with combined hyperlipidemia ( n = 29 ), the capacity of FMD was weaker whereas the levels of interleukin (IL)-lα, tumor necrosis factor alpha (TNF α ), soluble intercellular adhesion molecule (sICAM), and fibrinogen were higher compared to normolipemic controls with normal FMD adjusted for age and sex. Patients were randomized to a diet-only or to a ciprofibrate treatment group. After 8 weeks FMD levels rose significantly both in the diet-only (10.2%) and the ciprofibrate treatment (79.4%) groups. In the diet-only group improvement of FMD was significantly associated with the reduction of triglyceride (by 15.9%) and cholesterol (6.9%) levels. The much larger improvement of FMD due to ciprofibrate therapy was accompanied by significant reductions of cholesterol (by 14.4%), fibrinogen, IL-1α, and sICAM levels and by significant increase of high-density lipoprotein (HDL) cholesterol concentration, but the change in FMD correlated only with the reduction of the cholesterol level. In line with previous data the authors emphasize that improvement of FMD in patients with combined hyperlipidemia treated with diet and/or ciprofibrate is linked directly to the reduction of cholesterol and triglyceride concentrations rather than to changes in the level of the investigated inflammatory markers. [ABSTRACT FROM AUTHOR]

Abstract: Brown (BAT) and white (WAT) adipose tissues play a key role in the body energy balance orchestrated by the central nervous system. Hibernators have developed a seasonal obesity to respond to inhospitable environment. Jerboa is one of the deep hibernator originated from sub-desert highlands. Thus, this animal represents an excellent model to study cold adaptation mechanism. We report that the adipogenic factor PPARγ exhibits a differential expression between BAT and WAT at mRNA level. A specific induction was only seen in WAT of pre-hibernating jerboa. Interestingly, PPAR β/δ is specifically induced in BAT and brain of pre-hibernating jerboa, highlighting for the first time the possible key role of this ubiquitous isoform in the cold adaptation of this true hibernator. Inductions of PPARγ2 in WAT and PPAR β/δ in BAT are blunted by a hypolipemic drug, the ciprofibrate. These changes may be correlated with hibernation arrest and death of treated jerboa. Mitochondrial acyl-CoA dehydrogenase and peroxisomal acyl-CoA oxidase activities in brown and white adipose tissues are decreased up to 85% during cold acclimatization (without food privation). These enzyme activities are subject to a strong induction in BAT and in WAT (3.4–7.5 fold) during the hibernation period. The BAT thermogenesis marker is also largely induced (~4 fold of UCP1 mRNA level) during pre-hibernation period. Unexpectedly, treatment with ciprofibrate deeply affects lipolysis in BAT by increasing acyl-CoA dehydrogenase activity (3.4 fold) and acyl-CoA oxidase at both activity and mRNA levels (2.8 and 3.8 fold, respectively) and enhances strongly UCP1 mRNA level (9.5 fold) during pre-hibernation. [Copyright &y& Elsevier]

Peroxisome proliferators (PPs) are a diverse group of nongenotoxic compounds, which induce hepatic tumors in rodents. The mechanisms leading to hepatic tumors have not been elucidated, but oxidative stress may play a role in the process. Previous studies in our laboratory have shown that peroxisome proliferators activate the transcription factor nuclear factor-kappa B (NF-κB) and that this activation is mediated at least in part by oxidative stress. We therefore hypothesized that increased dietary vitamin E would decrease NF-κB DNA binding in rodents treated with ciprofibrate (CIP). In this study, 36 male Sprague–Dawley rats were fed a purified diet containing varying levels of vitamin E (10, 50, 250 ppm α-tocopherol acetate). After 28 days on the purified diet, seven animals per vitamin E group received 0.01% CIP in the diet for 10 days. Electrophoretic mobility shift assays (EMSAs) showed that CIP treatment increased DNA binding of NF-κB. Increased dietary α-tocopherol acetate inhibited CIP-induced NF-κB DNA binding. Because NF-κB translocates to the nucleus upon the phosphorylation and degradation of inhibitor of IκB, we also used Western blots to measure cytosolic protein levels of IκBα and IκBβ, and the IκB kinases, IKKα and IKKβ. IκBα protein levels were decreased in all three CIP-treated groups, with the 10 ppm vitamin E diet also decreasing IκBα levels in control rats. No difference in IκBβ protein levels was observed among any of the groups. The CIP-treated rats generally had lower protein levels of IKKα and IKKβ. This study supports our working hypothesis that an increased antioxidant environment can inhibit CIP-mediated NF-κB induction. [Copyright &y& Elsevier]

Gastrin-producing G cells constitute one of the major populations of neuroendocrine cells in the antral mucosa of the stomach. The peroxisome proliferator-activated receptor (PPAR) α-agonist ciprofibrate is used as a lipid-lowering drug. Recently, ciprofibrate has been shown to induce hypergastrinemia in rats without reducing gastric acidity, which indicates a direct stimulatory effect on the G cell. Gastrin probably plays an important role in gastric tumorgenesis, and long-term dosing with ciprofibrate results in enterochromaffin-like (ECL) cell carcinoids in the oxyntic mucosa of rats. In this study, we aimed to examine changes of neuroendocrine granules in G cells following ciprofibrate dosing and relate them to changes induced by the proton pump inhibitor pantoprazole. Furthermore, we wanted to study peroxisomes in G cells. Rats received ciprofibrate 80 mg/kg/day or pantoprazole 200 mg/kg/day in 4 weeks. Antral mucosal specimens were processed for conventional staining procedures and immunocytochemistry for both the light and electron micro-scope. Specimens were immunolabeled for gastrin and peroxisome-specific proteins. Electron micrographs were analyzed planimetrically. This study shows that hypergastrinemia induced by ciprofibrate is accompanied by a decrease in granule number per cell and a relative increase in electron-dense granules. These changes were quite similar to those induced by pantoprazole, indicating signs of G-cell activation in general. However, distinctions concerning granule size and composition and both hypertrophy and hyperplasia of G cells are presented. Finally, demonstration of peroxisomes in G cells was only achieved by using the highly sensitive tyramide signal amplification technique in immunostaining for the peroxisome-specific protein PMP-70. Therefore, neither morphological nor quantitative changes of peroxisomes in G cells were detected. [ABSTRACT FROM AUTHOR]

Aim: The action of ciprofibrate in hypertriglyceridemic patients is well established. Not only is ciprofibrate able to alter the lipid profile, but it can also change the values of fibrinogen, C-reactive protein, creatinine, transaminases, gamma-glutamyl transpeptidase and serum alkaline phosphatase. However, previous studies focused on the effect of ciprofibrate in hypertriglyceridemic patients, leaving unanswered the question of whether ciprofibrate exerts the same effect on hyperlipidemic patients with normal triglyceride values. The aim of this study is to answer this question.Methods: In this randomized clinical trial, 64 men and women with elevated cholesterol or triglyceride levels were included. Two subgroups were formed according to triglyceride levels: one (36 patients) with elevated triglyceride levels (> 200 mg/dL [2.26 mmol/L]) and another (28 patients) with normal triglyceride levels (< 200 mg/dL [2.26 mmol/l]). After a 6-week period of step 1 diet according to the National Cholesterol Education Program, ciprofibrate (100 mg once daily) was administered for 16 weeks. Primary efficacy points were the changes of lipid parameters (total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, triglycerides, apoproteins A1, B, E and lipoprotein [a], high sensitivity C reactive protein, fibrinogen, glucose, insulin, aspartate transaminase, alanine transaminase, gamma-glutamyl transpeptidase, alkaline phosphatase, urea and creatinine levels in a fasting blood sample before and after treatment with ciprofibrate.Results: The subgroup with triglyceride < 200 mg/dL (2.26 mmol/L): After the administration of ciprofibrate total cholesterol and low-density lipoprotein cholesterol were reduced by 15% (P < 0.001), and 19% (P < 0.001), respectively, while high-density lipoprotein cholesterol increased by 9% (P = 0.02). Apoproteins B and E levels were reduced by 21% (P < 0.001) and 11% (P = 0.002), respectively. Subgroup with triglyceride > 200 mg/dL (2.26 mmol/L): After the administration of ciprofibrate, no significant change in LDL cholesterol levels was observed. Total cholesterol levels were reduced by 15% (P < 0.001) and high-density lipoprotein cholesterol levels were increased by 13% (P = 0.004). Apoprotein B and apoprotein E levels were reduced by 16% (P < 0.001) and 30% (P < 0.001), respectively. Apoprotein-A1 levels were increased by 5% (P = 0.024). In the whole group of patients, the fibrinogen levels fell by 7% (P = 0.043), and the serum creatinine level increased by 10% (P < 0.001). This rise in serum creatinine was more pronounced in patients with low triglyceride levels (15% vs 5%, P = 0.009). Ciprofibrate decreased C-reactive protein levels by 26% in 44 patients who had C-reactive protein measurements (P < 0.001). gamma-glutamyl transpeptidase activity was similarly decreased (by approximately 40%) in both groups of patients. Alkaline phosphatase activity decreased in both groups, a reduction which was greater in hypertriglyceridemics (20% vs 10%, P = 0.004).Conclusions: Ciprofibrate improved some of the vascular risk factors, such as total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, apoproteins A1, B, and E, and fibrinogen levels in both hypertriglyceridemics and normotriglyceridemics. In addition, ciprofibrate raised the serum creatinine and improved the activity of the hepatic enzymes in the plasma in both patient subgroups. [ABSTRACT FROM AUTHOR]

Activated peroxisome proliferator activated receptor alpha (PPARα) protects against the cellular inflammatory response, and is central to fatty acid-mediated upregulation of the gene encoding the key ketogenic enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHS). We have previously demonstrated both PPARα and mHS expression in brain, implying that brain-targeted PPARα activators may likewise up-regulate mHS expression in brain. Thus, to attempt pharmacological activation of brain PPARα in vivo, we have administered to rats two drugs with previously defined actions in rat brain, namely the PPARα-selective activator ciprofibrate and the pan-PPAR activator valproate. Using the sensitive and discriminatory RNase protection co-assay, we demonstrate that both ciprofibrate and valproate induce mHS expression in liver, the archetypal PPARα-expressing organ. Furthermore, ciprofibrate potently increases mHS mRNA abundance in rat brain, together with lesser increases in two other PPARα-regulated mRNAs. Thus we demonstrate, for the first time, up-regulation of expression of PPARα-dependent genes including mHS in brain, with implications in the increased elimination of neuro-inflammatory lipids and concomitant increased production of neuro-protective ketone bodies. [Copyright &y& Elsevier]

Ciprofibrate (CIP) is a highly lipophilic and poorly water-soluble drug, typically used for dyslipidemia treatment. Although it is already commercialized in capsules, no previous studies report its solid-state structure; thus, information about the correlation with its physicochemical properties is lacking. In parallel, recent studies have led to the improvement of drug administration, including encapsulation in polymeric nanoparticles (NPs). Here, we present CIP's crystal structure determined by PXRD data. We also propose an encapsulation method for CIP in micelles produced from Pluronic P123/F127 and PEO-b-PCL, aiming to improve its solubility, hydrophilicity, and delivery. We determined the NPs' physicochemical properties by DLS, SLS, ELS, SAXS and the loaded drug amount by UV-Vis spectroscopy. Micelles showed sizes around 10–20 nm for Pluronic and 35–45 nm for the PEO-b-PCL NPs with slightly negative surface charge and successful CIP loading, especially for the latter; a substantial reduction in ζ-potential may be evidenced. For Pluronic nanoparticles, we scanned different conditions for the CIP loading, and its encapsulation efficiency was reduced while the drug content increased in the nanoprecipitation protocol. We also performed in vitro release experiments; results demonstrate that probe release is driven by Fickian diffusion for the Pluronic NPs and a zero-order model for PEO-b-PCL NPs. [ABSTRACT FROM AUTHOR]

Recent studies in mice harboring a targeted disruption of genes encoding TNF receptor 1 (TNFR-1) or Interleukin 6 (IL-6) suggested a critical role for TNF and IL-6 in initiation of liver regeneration after 2/3 partial hepatectomy. However, hepatocyte proliferation can also occur following treatment with agents that do not induce tissue loss (primary mitogens). To determine whether the above cytokines could also be involved in mitogen-induced liver cell proliferation, we studied the hepatocyte proliferative response after treatment with primary mitogens in mice knock-out for TNFR-1 or IL-6. Our results showed no difference in the proliferative response of the liver between the wild type and the knock-out mice following treatment with the mitogens 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), or the peroxisome proliferator, ciprofibrate, suggesting that TNF or IL-6 may not play a major role in this type of proliferation. Gel shift assay indicated that TCPOBOP-induced hepatocyte proliferation is not associated with activation of STAT3 transcription factor, a major target of IL-6 and other growth factors/cytokines. Our results thus indicate that hepatocyte proliferation can be induced by at least two different pathways; compensatory regeneration being TNF and IL-6-dependent, and mitogen-induced direct hyperplasia which does not require TNF or IL-6. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine the effect of the dietary antioxidant vitamin E on hepatocarcinogenesis by peroxisome proliferators which, it is hypothesized, induce tumors by increased production of hydrogen peroxide or other oxygen radicals. Rats were fed diets containing the peroxisome proliferator ciprofibrate and one of three concentrations (10, 50, or 500 ppm) of α-tocopheryl acetate for 6 months or 21 months. The incidence of hepatic tumors and the number and volume of γ-glutamyl-transpeptidase-positive, ATPase-negative, glucose-6-phosphatase-negative, and glucose-6-phosphatase-positive foci were quantified. No tumors or altered hepatic foci were seen at 6 months, but at 21 months the incidence of hepatic tumors and the number and volume of altered hepatic foci were increased in rats fed higher levels of vitamin E. Indices of oxidative damage - concentrations of malonaldehyde, conjugated dienes, and lipidsoluble fluorescence products - were not affected or were lower in rats fed higher amounts of vitamin E; the enhancing effect of vitamin E on the development of altered hepatic foci and hepatic tumors, therefore, was not related to the induction of cellular oxidative damage. Hepatic peroxisomal fatty acid Β-oxidation and vitamin C concentrations were not affected by vitamin E, whereas the glutathione concentration was decreased in rats fed higher amounts of vitamin E. This study shows that increasing the vitamin E content of the diet enhances ciprofibrate-induced hepatocarcinogenesis, but the mechanism of this effect is unclear. [ABSTRACT FROM AUTHOR]

Several hypolipidemic drugs, plasticizers, and other chemicals induce hepatic peroxisome proliferation and hepatocellular carcinomas in rodents. These agents induce and promote hepatocarcinogenesis by unknown mechanisms, since most studies have not found them to be genotoxic. Peroxisome proliferators increase the expression of several genes, including those for the enzymes of the peroxisomal β-oxidation path-way and the cytochrome P-450 4A family, which metabolize lipids, including eicosanoids and their precursor fatty acids. The peroxisome proliferators ciprofibrate and perfluorodecanoic acid (PFDA) were therefore examined for their ability to alter hepatic eicosanoid concentrations. Rats received injections of 3 or 10 mg PFDA/kg body weight every 14 days or were fed 0.01% ciprofibrate for 10 days, 24 days, 6 weeks, 26 weeks, or 54 weeks. The activity of the peroxisomal enzyme fatty acyl CoA oxidase was significantly increased by both ciprofibrate and PFDA at all times. Hepatic concentrations of prostaglandins E and F (PGE, PGF) thromboxane B (TXB), and leukotriene C (LTC) were measured by immunoassay. Concentrations of PGE, PGF, and TXB were decreased in livers of rats receiving ciprofibrate or PFDA compared to livers of control rats, with ciprofibrate exerting a greater effect than PFDA at the doses used. Hepatic LTC concentrations were significantly increased by ciprofibrate at 10 days and PFDA at 54 weeks, and significantly decreased by PFDA at 26 weeks. These alterations in eicosanoid concentrations may be important in the natural history of peroxisome proliferator-induced hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]

Chronic ciprofibrate administration resulted in distinct differences in hepatic responses between the two species examined. In the rat, hepatomegaly was observed with the coordinate induction of carnitine acetyltransferase, peroxisomal β-oxidation and cytochrome P450IVA1 activities. The latter induction of cytochrome P450IVA1-dependent fatty acid hydroxylase activity was specific to this cytochrome P450 sub family, as ciprofibrate pretreatment resulted in an inhibition of the enzyme activities associated with the cytochrome P450 IIB and IA sub-families. Induction of mitochondrial enzymes were also noted in the rat, but at a substantially lower level than the microsomal and peroxisomal enzyme changes noted above. The majority of these enzyme changes were reversible in the rat after a 4-week, inducer-free period. In contrast, the marmoset displayed a different pattern of enzyme changes in response to ciprofibrate and at the high dose level, inhibition of microsomal fatty acid hydroxylase activity was observed in addition to no change in carnitine acetyltransferase activitiy. Although peroxisomal β-oxidation activity was induced in the marmoset, the specific activity was 10-fold lower than in the rat, concomitant with only minimum changes in the liver: body weight ratio. Taken collectively, our data have demonstrated that the marmoset is relatively refractory to ciprofibrate-induced liver enzyme changes with the implication that the extrapolation of the associated hepatotoxicity clearly documented in rodents must be viewed with extreme caution in non-human primates. [ABSTRACT FROM AUTHOR]

Peroxisome proliferators induce hepatic peroxisome proliferation and hepatic tumors in rodents. These chemicals increase the expression of the peroxisomal β-oxidation pathway and the cytochrome P-450 4A family, which metabolizes lipids, including eicosanoids. Peroxisome proliferators transiently induce increased cell proliferation in vivo. However, peroxisome proliferators are weakly mitogenic and are not co-mitogenic with epidermal growth factor (EGF) in cultured hepatocytes. Earlier study found that the peroxisome proliferator ciprofibrate is comitogenic with eicosanoids. In order to study possible mechanisms of the comitogenicity of peroxisome proliferator ciprofibrate and eicosanoids, we hypothesized that the co-mitogenicity may result from synergistic or additive increases of second messengers in mitogenic signal pathways. We therefore examined the effect of the peroxisome proliferator ciprofibrate, prostaglandin F2α (PGF2α) and the combination of ciprofibrate and PGF2α with or without growth factors on the protein kinase C (PKC) activity, and inositol-1, 4, 5-triphosphate (IP3) and intracellular calcium ([Ca2+]i) concentrations in cultured rat hepatocytes. The combination of ciprofibrate and PGF2α significantly increased particulate PKC activity. The combination of ciprofibrate and PGF2α also significantly increased EGF, transforming growth factor-α (TGF-α) and hepatic growth factor (HGF)-induced particulate PKC activity. The combination of ciprofibrate and PGF2α greatly increased [Ca2+]i. However, the increases of PKC activity and [Ca2+]i by ciprofibrate and PGF2α alone were much smaller. Neither ciprofibrate or PGF2α alone nor the combination of ciprofibrate and PGF2α significantly increased the formation of IP3. The combination of ciprofibrate and PGF2α, however, blocked the inhibitory effect of TGF-β on particulate PKC activity and formation of IP3 induced by EGF. These results show that co-mitogenicity of the peroxisome proliferator ciprofibrate and eicosanoids may result from the increase in particulate PKC activity and intracellular calcium concentration but not from the formation of IP3. [ABSTRACT FROM AUTHOR]

Abstract Background Hypertriglyceridemia in combination with low HDL cholesterol levels is a risk factor for cardiovascular disease. Our objective was to evaluate the efficacy of ciprofibrate for the treatment of this form of dyslipidemia and to identify factors associated with better treatment response. Methods Multicenter, international, open-label study. Four hundred and thirty seven patients were included. The plasma lipid levels at inclusion were fasting triglyceride concentrations between 1.6–3.9 mM/l and HDL cholesterol ≤ 1.05 mM/l for women and ≤ 0.9 mM/l for men. The LDL cholesterol was below 4.2 mM/l. All patients received ciprofibrate 100 mg/d. Efficacy and safety parameters were assessed at baseline and at the end of the treatment. The primary efficacy parameter of the study was percentage change in triglycerides from baseline. Results After 4 months, plasma triglyceride concentrations were decreased by 44% (p < 0.001). HDL cholesterol concentrations were increased by 10% (p < 0.001). Non-HDL cholesterol was decreased by 19%. A greater HDL cholesterol response was observed in lean patients (body mass index < 25 kg/m2) compared to the rest of the population (8.2 vs 19.7%, p < 0.001). In contrast, cases with excess body weight had a larger decrease in non-HDL cholesterol levels (-20.8 vs -10.8%, p < 0.001). There were no significant complications resulting from treatment with ciprofibrate. Conclusions Ciprofibrate is efficacious for the correction of hypertriglyceridemia / low HDL cholesterol. A greater decrease in non-HDL cholesterol was found among cases with excess body weight. The mechanism of action of ciprofibrate may be influenced by the pathophysiology of the disorder being treated.