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Howard P. Glauert - One of the best experts on this subject based on the ideXlab platform.
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Cell Proliferation and Apoptosis Are Altered in Mice Deficient in the NF-κB p50 Subunit after Treatment with the Peroxisome Proliferator Ciprofibrate
Toxicological sciences : an official journal of the Society of Toxicology, 2003Co-Authors: Job C. Tharappel, Howard P. Glauert, Aysegul Nalca, Aaron B. Owens, Leila Ghabrial, Elizabeth C. Konz, Brett T. SpearAbstract:We previously showed that the peroxisome proliferator Ciprofibrate increases hepatic NF-κB DNA binding activity in rats, mice, and hepatoma cell lines. Here, we analyzed the response to Ciprofibrate in mice that lack the NF-κB p50 gene (p50 -/- ). Wild-type and p50 -/- mice were fed a diet with or without 0.01% Ciprofibrate for 10 days. NF-κB DNA binding activity was present and increased after Ciprofibrate treatment in wild-type mice, but was not detected in p50 -/- mice. The untreated p50 -/- mice had a higher level of hepatic cell proliferation, as measured by BrdU labeling, than did untreated wild-type mice. However, the increase in proliferation was greater in Ciprofibrate-fed wild-type mice than in Ciprofibrate-fed p50 -/- mice. The apoptotic index was low in wild-type mice in the presence or absence of Ciprofibrate. Apoptosis was increased in untreated p50 -/- mice compared to wild-type mice; apoptosis was reduced in p50 -/- mice after Ciprofibrate feeding. The c-Jun and JunB mRNA levels were higher in untreated p50 -/- mice than in untreated control mice; c-Jun mRNA levels increased, whereas JunB mRNA levels decreased in both groups after Ciprofibrate treatment. The c-Jun and JunB protein levels were the same in untreated wild-type and p50 -/- mice and increased in both groups after Ciprofibrate treatment. Several apoptosis-related mRNAs were higher in untreated p50 -/- mice compared to untreated control mice; expression of these genes increased in both groups after Ciprofibrate treatment. These data indicate that NF-κB contributes to the proliferative and apoptotic changes that occur in the liver in response to Ciprofibrate.
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Liver-specific catalase expression in transgenic mice inhibits NF-kappaB activation and DNA synthesis induced by the peroxisome proliferator Ciprofibrate.
Carcinogenesis, 1998Co-Authors: Vani Nilakantan, Brett T. Spear, Howard P. GlauertAbstract:Peroxisome proliferators are a group of non-genotoxic hepatic carcinogens that have been proposed to act by increasing oxidative damage in the liver. To test this hypothesis, we have examined if hepatic catalase overexpression in peroxisome proliferator-treated mice influences the induction of cell proliferation or the activation of transcription factors involved in cell proliferation. Transgenic mice or non-transgenic littermates were fed either 0.01% Ciprofibrate or a control diet for 21 days. Fatty acyl CoA oxidase activity was not significantly affected by catalase overexpression, although the ratio of fatty acyl CoA oxidase to catalase was significantly decreased in transgenic animals. The labeling index in hepatocytes was significantly increased by Ciprofibrate in non-transgenic mice, but catalase overexpression significantly inhibited this increase. Ciprofibrate increased the activation of nuclear factor (NF)-κB in non-transgenic mice, but this increase was inhibited by catalase overexpression. Ciprofibrate also increased AP-1 activation, but catalase overexpression did not significantly inhibit this increase, although AP-1 activation was 40% lower in transgenic mice. These results support the hypothesis that active oxygen plays a role in the induction of cell proliferation by the peroxisome proliferator Ciprofibrate and therefore may be important in the carcinogenicity of these agents.
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Effect of the peroxisome proliferator Ciprofibrate on hepatic cyclooxygenase and phospholipase A2 in rats
Toxicology, 1998Co-Authors: Lai K. Leung, Howard P. GlauertAbstract:Abstract Peroxisome proliferators, which include several hypolipidemic drugs, plasticizers and other chemicals, induce hepatic tumors in rodents. These chemicals alter the expression of enzymes involved in lipid metabolism, such as the cytochrome P450 4A family and peroxisomal β-oxidation enzymes. Previous studies have shown that the peroxisome proliferator Ciprofibrate reduces eicosanoid concentrations in rat livers and primary hepatocyte cultures, yet the mechanism is still unclear. In this study we examined cyclooxygenases 1 and 2 (COX-1 and COX-2) and cytosolic phospholipase A2 (cPLA2) to determine whether the rate-limiting enzymes in the eicosanoid synthetic pathway are altered by Ciprofibrate. Rats were fed 0.01% Ciprofibrate for 3, 6, or 10 days. Western analysis revealed that COX-2 protein was induced by Ciprofibrate (up to 13-fold at day 10), but that calcium-dependent (Ca-D) cPLA2 protein was not different from controls. The enzyme activity of calcium-independent (Ca-I) cPLA2 in Ciprofibrate-treated rats was increased 2-fold, whereas Ca-D cPLA2 and total COX activities were not affected. Using enzyme kinetics, we found that COX-1 (Ki=143 μM) and Ca-I cPLA2 (Ki=121 μM) were competitively inhibited by Ciprofibrate, but the inhibition was not physiologically significant. COX-2 and Ca-D cPLA2 were not inhibited by Ciprofibrate. These results show that Ciprofibrate increases Ca-I cPLA2 enzyme activity and COX-2 protein expression.
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Effect of the peroxisome proliferator Ciprofibrate on lipid peroxidation and 8-hydroxydeoxyguanosine formation in transgenic mice with elevated hepatic catalase activity.
Free radical biology & medicine, 1998Co-Authors: Vani Nilakantan, Brett T. Spear, Howard P. GlauertAbstract:Peroxisome proliferators are a group of non-genotoxic hepatic carcinogens which have been proposed to act by increasing oxidative damage in the liver. To test this hypothesis, we have produced a transgenic mouse line that has elevated catalase activity specifically in the liver. In this study, we have examined if catalase overexpression influences the induction of lipid peroxidation or oxidative DNA damage, two mechanisms which have been hypothesized to be important in the carcinogenesis by peroxisome proliferators. Transgenic mice or non-transgenic litter mates were fed either 0.01% Ciprofibrate or a control diet for 21 days. The activities of fatty acyl CoA oxidase and lauric acid hydroxylase were not significantly affected by catalase overexpression, although the ratio of fatty acyl CoA oxidase to catalase was significantly decreased in transgenic animals. Hepatic lipid peroxidation was estimated by quantifying the concentrations of malondialdehyde and conjugated dienes. Ciprofibrate treatment did not affect either endpoint, but catalase overexpression increased the concentrations of malondialdehyde (in untreated mice only) and conjugated dienes (in both untreated and Ciprofibrate-fed mice). Oxidative DNA damage was estimated by quantifying 8-hydroxydeoxyguanosine (8-OHdG) by high-performance liquid chromatography/electrochemical detection. Ciprofibrate treatment significantly increased hepatic 8-OHdG concentrations, in agreement with several previous studies, but catalase overexpression did not significantly affect them, although 8-OHdG concentrations were decreased 50% in untreated mice. These results imply that the metabolism of hydrogen peroxide by catalase is not an important factor in the development of hepatic lipid peroxidation. The decrease in hepatic 8-OHdG in untreated transgenic mice and the increase seen after Ciprofibrate administration imply that hydrogen peroxide is important in the formation of 8-OHdG. While the lack of decreased 8-OHdG levels in Ciprofibrate-treated transgenic mice does not support this conclusion, it is possible that catalase levels were not sufficiently high to affect this endpoint. Transgenic mice with higher hepatic catalase activities may be required to resolve this issue.
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Comitogenicity of eicosanoids and the peroxisome proliferator Ciprofibrate in cultured rat hepatocytes.
Journal of cellular physiology, 1996Co-Authors: Jin Tae Hong, Howard P. GlauertAbstract:Several hypolipidemic drugs and environmental contaminants induce hepatic peroxisome proliferation and hepatic tumors when administered to rodents. These chemicals increase the expression of the peroxisomal beta-oxidation pathway and the cytochrome P-450 4A family, which metabolize lipids, including eicosanoids and their precursor fatty acids. We previously found that the peroxisome proliferator Ciprofibrate decreases the level of eicosanoids in the liver and in cultured hepatocytes. In this study, we examined the effect of prostaglandins E2 and F2 alpha (PGE2 and PGF2 alpha), leukotriene C4 (LTC4) and the peroxisome proliferator Ciprofibrate on DNA synthesis in cultured hepatocytes. Primary rat hepatocytes were cultured on collagen gels in serum-free L-15 medium with varying concentrations of eicosanoids and Ciprofibrate, and the absence or presence of growth factors. Ciprofibrate lowered hepatocyte eicosanoid concentrations; the addition of eicosanoids restored their levels. After a 48-h exposure with [3H]-thymidine, DNA synthesis was determined by measuring [3H]-thymidine incorporation into DNA. The addition of PGE2, PGF2 alpha, and LTC4 to cultures along with Ciprofibrate increased DNA synthesis, whereas treatment with Ciprofibrate or eicosanoids alone resulted in a much smaller increase. The addition of epidermal growth factor (EGF) to the eicosanoid-Ciprofibrate combination increased DNA synthesis more than EGF or the eicosanoid-Ciprofibrate combination alone. The PGF2 alpha-Ciprofibrate combination also was comitogenic with transforming growth factor-alpha and hepatocyte growth factor. The addition of both Ciprofibrate and prostaglandins also blocked the growth inhibitory effect of transforming growth factor-beta on DNA synthesis induced by EGF. These results show that the eicosanoids PGE2, PGF2 alpha, and LTC4 are comitogenic with the peroxisome proliferator Ciprofibrate in cultured rat hepatocytes.
Dimitri P. Mikhailidis - One of the best experts on this subject based on the ideXlab platform.
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Effect of Ciprofibrate on Lipoproteins, Fibrinogen, Renal Function, and Hepatic Enzymes
2016Co-Authors: Evangelos C. Rizos, Dimitri P. Mikhailidis, Eleni Bairaktari, Emmanouel Ganotakis, Vasilios Tsimihodimos, Moses ElisafAbstract: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-reac-tive protein, creatinine, transaminases, y-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 hyperlipidem-ic 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 lev-els: one (36 patients) with elevated triglyceride levels (> 200 mg/dL [2.26 mmolIL]) 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, ciprofi-brate (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 den-sity lipoprotein cholesterol, triglycerides, apoproteins Al, B, E and lipoprotein [a], high sen-sitivity C reactive protein, fibrinogen, glucose, insulin, aspartate transaminase, alanin
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Effect of Ciprofibrate on lipoproteins, fibrinogen, renal function, and hepatic enzymes.
Journal of cardiovascular pharmacology and therapeutics, 2002Co-Authors: Evangelos C. Rizos, Dimitri P. Mikhailidis, Eleni Bairaktari, Emmanouel Ganotakis, Vasilios Tsimihodimos, Moses ElisafAbstract: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, y-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 mmolIL]) 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...
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Ciprofibrate versus gemfibrozil in the treatment of mixed hyperlipidemias : An open-label, multicenter study
Metabolism: clinical and experimental, 2001Co-Authors: Dimitri P. Mikhailidis, I. Anita JagroonAbstract:Abstract Mixed hyperlipidemia is a common risk factor for cardiovascular disease. The aim of this trial was to evaluate the efficacy and safety of Ciprofibrate versus gemfibrozil for the treatment of patients with mixed hyperlipidemia carefully selected for similar lipid profiles. A total of 68 patients who had mixed hyperlipidemia after following an isocaloric American Heart Association (AHA) phase I diet for 4 weeks were included. The plasma lipid levels at the inclusion were low-density lipoprotein-cholesterol (LDL-C) [ge ] 130 mg/dL, cholesterol [ge ] 240 mg/dL, and triglycerides [ge ] 200 mg/dL. Patients were randomly assigned to receive Ciprofibrate 100 mg/d or gemfibrozil 1,200 mg/d. At the end of the 8-week treatment period, efficacy and safety parameters were compared with baseline values. The primary efficacy parameters of the study were percentage changes in triglycerides and LDL-C from baseline. After 8 weeks, plasma triglyceride concentrations were decreased by 43.5% and 54% compared with baseline during Ciprofibrate and gemfibrozil therapy, respectively ( P [lt ] .001). High-density lipoprotein-cholesterol (HDL-C) concentrations were increased 20.8% and 19.3% during Ciprofibrate and gemfibrozil, respectively ( P [lt ] .001). Apoprotein B, cholesterol, and very[mdash ]low-density lipoprotein-cholesterol (VLDL-C) concentrations were also improved by the study drugs (18.6%, 13.2%, and 30.9%, respectively, during Ciprofibrate and 44%, 13.8%, and 14.4%, respectively, during gemfibrozil). Meanwhile, the effect of the drug was minimal on LDL-C. A significant decrease in non[mdash ]HDL-C resulted from both treatments (19% and 19.5%, respectively, P [lt ] .05). The only statistically significant difference observed between treatments was the effects on fibrinogen concentration, a coronary risk factor. Ciprofibrate significantly decreased its concentration by 18.8%, fibrinogen was slightly increased during gemfibrozil treatment. No patient had a significant modification on any of the safety tests. In summary, Ciprofibrate and gemfibrozil are well-tolerated and efficacious treatments for mixed hyperlipidemia. Significant reductions in triglycerides, non[mdash ]HDL-C, and apolipoprotein B were achieved with both drugs. A significant fibrinogen reduction was obtained with Ciprofibrate.
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Statin + fibrate combination therapy: Fluvastatin with bezafibrate or Ciprofibrate in high risk patients with vascular disease
International journal of cardiology, 1999Co-Authors: J. A. Papadakis, Emanuel S Ganotakis, Indera Anita Jagroop, Anthony F. Winder, Dimitri P. MikhailidisAbstract:We evaluated the use of combination therapy (Ciprofibrate 100 mg or bezafibrate 400 mg plus fluvastatin 40 mg) in 23 patients (n=13 in the Ciprofibrate group) with established cardiovascular disease. Both treatments achieved a significant (P less than or equal to 0.01) decrease in the total cholesterol (TC) (32 and 21%), triglycerides (TG) (53 and 46%) and low-density lipoprotein (LDL) (36 and 26%) levels and the TC/high-density Lipoprotein (HDL) (42 and 31%) and LDL/HDL (46 and 35%) ratios. HDL levels were increased (19% for both treatment groups), but this rise only achieved significance (P=0.01) in the Ciprofibrate group. Although the two patient groups were not strictly matched, the reduction in serum TC and LDL levels was greater with Ciprofibrate (32 and 36%, respectively; P less than or equal to 0.001) than with bezafibrate (21 and 26%, respectively; P less than or equal to 0.01). There was a significant reduction in plasma fibrinogen levels (36.4 and 13.5% in the Ciprofibrate and bezafibrate group, respectively). None of the patients reported myalgia or had abnormal creatine kinase activity or liver function tests. Combination therapy is worth considering in high-risk patients because of the advantages associated with this option, Combination therapy is competitively priced when compared with high doses of statins. An end-point-based trial is needed. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.
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statin fibrate combination therapy fluvastatin with bezafibrate or Ciprofibrate in high risk patients with vascular disease
International Journal of Cardiology, 1999Co-Authors: J. A. Papadakis, Emanuel S Ganotakis, Indera Anita Jagroop, Anthony F. Winder, Dimitri P. MikhailidisAbstract:We evaluated the use of combination therapy (Ciprofibrate 100 mg or bezafibrate 400 mg plus fluvastatin 40 mg) in 23 patients (n=13 in the Ciprofibrate group) with established cardiovascular disease. Both treatments achieved a significant (P less than or equal to 0.01) decrease in the total cholesterol (TC) (32 and 21%), triglycerides (TG) (53 and 46%) and low-density lipoprotein (LDL) (36 and 26%) levels and the TC/high-density Lipoprotein (HDL) (42 and 31%) and LDL/HDL (46 and 35%) ratios. HDL levels were increased (19% for both treatment groups), but this rise only achieved significance (P=0.01) in the Ciprofibrate group. Although the two patient groups were not strictly matched, the reduction in serum TC and LDL levels was greater with Ciprofibrate (32 and 36%, respectively; P less than or equal to 0.001) than with bezafibrate (21 and 26%, respectively; P less than or equal to 0.01). There was a significant reduction in plasma fibrinogen levels (36.4 and 13.5% in the Ciprofibrate and bezafibrate group, respectively). None of the patients reported myalgia or had abnormal creatine kinase activity or liver function tests. Combination therapy is worth considering in high-risk patients because of the advantages associated with this option, Combination therapy is competitively priced when compared with high doses of statins. An end-point-based trial is needed. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.
J. A. Papadakis - One of the best experts on this subject based on the ideXlab platform.
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Statin + fibrate combination therapy: Fluvastatin with bezafibrate or Ciprofibrate in high risk patients with vascular disease
International journal of cardiology, 1999Co-Authors: J. A. Papadakis, Emanuel S Ganotakis, Indera Anita Jagroop, Anthony F. Winder, Dimitri P. MikhailidisAbstract:We evaluated the use of combination therapy (Ciprofibrate 100 mg or bezafibrate 400 mg plus fluvastatin 40 mg) in 23 patients (n=13 in the Ciprofibrate group) with established cardiovascular disease. Both treatments achieved a significant (P less than or equal to 0.01) decrease in the total cholesterol (TC) (32 and 21%), triglycerides (TG) (53 and 46%) and low-density lipoprotein (LDL) (36 and 26%) levels and the TC/high-density Lipoprotein (HDL) (42 and 31%) and LDL/HDL (46 and 35%) ratios. HDL levels were increased (19% for both treatment groups), but this rise only achieved significance (P=0.01) in the Ciprofibrate group. Although the two patient groups were not strictly matched, the reduction in serum TC and LDL levels was greater with Ciprofibrate (32 and 36%, respectively; P less than or equal to 0.001) than with bezafibrate (21 and 26%, respectively; P less than or equal to 0.01). There was a significant reduction in plasma fibrinogen levels (36.4 and 13.5% in the Ciprofibrate and bezafibrate group, respectively). None of the patients reported myalgia or had abnormal creatine kinase activity or liver function tests. Combination therapy is worth considering in high-risk patients because of the advantages associated with this option, Combination therapy is competitively priced when compared with high doses of statins. An end-point-based trial is needed. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.
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statin fibrate combination therapy fluvastatin with bezafibrate or Ciprofibrate in high risk patients with vascular disease
International Journal of Cardiology, 1999Co-Authors: J. A. Papadakis, Emanuel S Ganotakis, Indera Anita Jagroop, Anthony F. Winder, Dimitri P. MikhailidisAbstract:We evaluated the use of combination therapy (Ciprofibrate 100 mg or bezafibrate 400 mg plus fluvastatin 40 mg) in 23 patients (n=13 in the Ciprofibrate group) with established cardiovascular disease. Both treatments achieved a significant (P less than or equal to 0.01) decrease in the total cholesterol (TC) (32 and 21%), triglycerides (TG) (53 and 46%) and low-density lipoprotein (LDL) (36 and 26%) levels and the TC/high-density Lipoprotein (HDL) (42 and 31%) and LDL/HDL (46 and 35%) ratios. HDL levels were increased (19% for both treatment groups), but this rise only achieved significance (P=0.01) in the Ciprofibrate group. Although the two patient groups were not strictly matched, the reduction in serum TC and LDL levels was greater with Ciprofibrate (32 and 36%, respectively; P less than or equal to 0.001) than with bezafibrate (21 and 26%, respectively; P less than or equal to 0.01). There was a significant reduction in plasma fibrinogen levels (36.4 and 13.5% in the Ciprofibrate and bezafibrate group, respectively). None of the patients reported myalgia or had abnormal creatine kinase activity or liver function tests. Combination therapy is worth considering in high-risk patients because of the advantages associated with this option, Combination therapy is competitively priced when compared with high doses of statins. An end-point-based trial is needed. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.
Norbert Latruffe - One of the best experts on this subject based on the ideXlab platform.
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Sensitivity of liver metabolism in jerboa (Jaculus orientalis) to Ciprofibrate, a peroxisome proliferator.
Mol Med Report, 2009Co-Authors: Driss Mountassif, Norbert Latruffe, Mostafa Kabine, Karima Mounchid, Khadija Mounachi, M'hammed Saïd El KebbajAbstract:Ciprofibrate is a well-known drug used to normalize lipid parameters and fibrinogen in atherosclerosis patients. In laboratory rodents such as rats or mice, Ciprofibrate exhibits peroxisome proliferator activity. However, to date, no clear alterations or side effects caused by Ciprofibrate have been noted in humans. In order to further investigate such possible relationships, we studied the effects of sustained Ciprofibrate treatment in jerboas (Jaculus orientalis). In these rodents, Ciprofibrate does not induce hepatomegaly or promote liver cell DNA replication, confirming that this species more closely resembles humans than do rats or mice. The jerboas were treated daily with Ciprofibrate at 3 mg/kg body weight for 4 weeks. Subcellular markers, clinical enzymes and enzymatic antioxidant defenses were then assessed. The results showed a strong decrease in peroxisomal catalase activity and an increase in the level of malondialdehyde (a stress biomarker). Moreover, Ciprofibrate in vivo and in vitro inhibited D-3-hydroxybutyrate dehydrogenase, a mitochondrial enzyme of the ketone body interconversion that is important in redox balance (NAD+/NADH+H+ ratio). In conclusion, under these conditions, Ciprofibrate induced alterations in the liver oxidative metabolism.
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Difference between guinea pig and rat in the liver peroxisomal response to equivalent plasmatic level of Ciprofibrate.
Archives of biochemistry and biophysics, 1996Co-Authors: Corinne Pacot, Michel Petit, Michel Rollin, Ninoufar Behechti, Maryvonne Moisant, Paul Deslex, Jürgen Althoff, Jean Claude Lhuguenot, Norbert LatruffeAbstract:Abstract Guinea pig was previously classified as a species nonresponsive to peroxisome proliferators. However, none of the previous reports was based on pharmacokinetic data. Here, after a comparative pharmacokinetic study between guinea pig and rat, we evaluate the guinea pig liver peroxisomal response to Ciprofibrate, a hypolipemic agent and a potent peroxisome proliferator in rat. (1) Pharmacokinetic results show that plasmatic concentrations of Ciprofibrate are equivalent in guinea pig and rat when guinea pigs are treated with Ciprofibrate at 30 mg/kg twice a day and rats are treated at 3 mg/kg once a day. (2) The treatment of guinea pigs at 30 mg/kg twice a day for 2 weeks leads to a significant increase in the liver peroxisomal palmitoyl-CoA oxidase activity (×1.6) and also in the microsomal ω-laurate hydroxylase activity (×1.8). These increases are in accordance with the changes in polypeptide patterns of isolated liver peroxisomes as well as in the immunoblotting of acyl-CoA oxidase. It is deduced that a weak, but significant, peroxisome proliferation can occur in guinea pig liver after a Ciprofibrate treatment at dosages corresponding to equivalent plasmatic concentrations of the drug between guinea pig and rat. (3) The hybridization of guinea pig liver RNA with the rat liver-inducible acyl-CoA oxidase cDNA probe shows a decrease in the corresponding heterologuous mRNA content after treatment with Ciprofibrate at 30 mg/kg twice a day. This result contrasts with the slight increase observed in immunodetection and in enzymatic assays, suggesting the existence of at least two different acyl-CoA oxidases in guinea pig liver peroxisomes.
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Delayed effects of Ciprofibrate on rat liver peroxisomal properties and proto-oncogene expression
Biochemical pharmacology, 1995Co-Authors: Olivier Bardot, Mustapha Cherkaoui Malki, Marie-claude Clémencet, Norbert LatruffeAbstract:Peroxisome proliferators (PPs) are non-genotoxic carcinogens in rodents. Their reversible effects on rat liver have been studied with Ciprofibrate and fenofibrate. We found that with the hypolipemic drug fenofibrate a pause of 28 days is sufficient for a return to normal status, whereas with the highly potent PP Ciprofibrate, the stimulation of ACO mRNA levels remains after its withdrawal. We investigated the effects of the renewal of the treatment with PPs on other peroxisomal parameters and proto-oncogene expression using Wistar rats. Interestingly, c-myc expression was enhanced even upon drug withdrawal, and was more stimulated by the second exposure to Ciprofibrate, while c-fos expression was unaltered. However, only slight differences in c-Ha-ras expression were observed. Therefore, the effects of PPs in the Wistar rats are not totally reversible within 28 days following withdrawal, depending on the drug used. These delayed effects of Ciprofibrate could be a key to our understanding the hepatocarcinogenic effect of PPs in rodents.
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Transcriptional and post-transcriptional analysis of peroxisomal protein encoding genes from rat treated with an hypolipemic agent, Ciprofibrate. Effect of an intermittent treatment and influence of obesity.
Biochemical pharmacology, 1995Co-Authors: Françoise Caira, Corinne Pacot, Olivier Bardot, Mustapha Cherkaoui Malki, Norbert LatruffeAbstract:The treatment of rats with Ciprofibrate, a potent peroxisome proliferator, led to increased levels of the peroxisomal acyl-CoA oxidase (ACO) mRNA. How Ciprofibrate functions to elevate ACO mRNA is not known. To help determine the mechanism of Ciprofibrate action, in vitro transcription assays were performed. It was determined that Ciprofibrate was responsible for a 3.5-fold stimulation of the rate of ACO transcription within 24 hr of ingestion. It was also observed that the transcription rate stimulation following a 2-week Ciprofibrate treatment of Wistar rats was maintained following 4 weeks of Ciprofibrate withdrawal. Re-introduction of the drug after the 4-week pause resulted in greater stimulation than was initially observed. The results demonstrate that the effect of Ciprofibrate is rapid and persists at least twice as long as the initial treatment period. In Zucker rats, both lean and obese, ACO mRNA levels were examined following 2 weeks of Ciprofibrate treatment (1 or 3 mg/kg body weight/day). The presence of increased blood levels of triglycerides did not increase Ciprofibrate action on transcription, although basal levels of transcription of peroxisomal enzymes were higher in obese rats. The increase in the ACO mRNA level was greater than the transcription rate stimulation suggesting a post-transcriptional regulation.
Indera Anita Jagroop - One of the best experts on this subject based on the ideXlab platform.
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Statin + fibrate combination therapy: Fluvastatin with bezafibrate or Ciprofibrate in high risk patients with vascular disease
International journal of cardiology, 1999Co-Authors: J. A. Papadakis, Emanuel S Ganotakis, Indera Anita Jagroop, Anthony F. Winder, Dimitri P. MikhailidisAbstract:We evaluated the use of combination therapy (Ciprofibrate 100 mg or bezafibrate 400 mg plus fluvastatin 40 mg) in 23 patients (n=13 in the Ciprofibrate group) with established cardiovascular disease. Both treatments achieved a significant (P less than or equal to 0.01) decrease in the total cholesterol (TC) (32 and 21%), triglycerides (TG) (53 and 46%) and low-density lipoprotein (LDL) (36 and 26%) levels and the TC/high-density Lipoprotein (HDL) (42 and 31%) and LDL/HDL (46 and 35%) ratios. HDL levels were increased (19% for both treatment groups), but this rise only achieved significance (P=0.01) in the Ciprofibrate group. Although the two patient groups were not strictly matched, the reduction in serum TC and LDL levels was greater with Ciprofibrate (32 and 36%, respectively; P less than or equal to 0.001) than with bezafibrate (21 and 26%, respectively; P less than or equal to 0.01). There was a significant reduction in plasma fibrinogen levels (36.4 and 13.5% in the Ciprofibrate and bezafibrate group, respectively). None of the patients reported myalgia or had abnormal creatine kinase activity or liver function tests. Combination therapy is worth considering in high-risk patients because of the advantages associated with this option, Combination therapy is competitively priced when compared with high doses of statins. An end-point-based trial is needed. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.
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statin fibrate combination therapy fluvastatin with bezafibrate or Ciprofibrate in high risk patients with vascular disease
International Journal of Cardiology, 1999Co-Authors: J. A. Papadakis, Emanuel S Ganotakis, Indera Anita Jagroop, Anthony F. Winder, Dimitri P. MikhailidisAbstract:We evaluated the use of combination therapy (Ciprofibrate 100 mg or bezafibrate 400 mg plus fluvastatin 40 mg) in 23 patients (n=13 in the Ciprofibrate group) with established cardiovascular disease. Both treatments achieved a significant (P less than or equal to 0.01) decrease in the total cholesterol (TC) (32 and 21%), triglycerides (TG) (53 and 46%) and low-density lipoprotein (LDL) (36 and 26%) levels and the TC/high-density Lipoprotein (HDL) (42 and 31%) and LDL/HDL (46 and 35%) ratios. HDL levels were increased (19% for both treatment groups), but this rise only achieved significance (P=0.01) in the Ciprofibrate group. Although the two patient groups were not strictly matched, the reduction in serum TC and LDL levels was greater with Ciprofibrate (32 and 36%, respectively; P less than or equal to 0.001) than with bezafibrate (21 and 26%, respectively; P less than or equal to 0.01). There was a significant reduction in plasma fibrinogen levels (36.4 and 13.5% in the Ciprofibrate and bezafibrate group, respectively). None of the patients reported myalgia or had abnormal creatine kinase activity or liver function tests. Combination therapy is worth considering in high-risk patients because of the advantages associated with this option, Combination therapy is competitively priced when compared with high doses of statins. An end-point-based trial is needed. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.