Toxicological effects of clofibric acid and diclofenac on plasma thyroid hormones of an Indian major carp, Cirrhinus mrigala during short and long-term exposures.

In the present investigation, the toxicity of most commonly detected pharmaceuticals in the aquatic environment namely clofibric acid (CA) and diclofenac (DCF) was investigated in an Indian major carp Cirrhinus mrigala. Fingerlings of C. mrigala were exposed to different concentrations (1, 10 and 100µgL(-1)) of CA and DCF for a period of 96h (short term) and 35 days (long term). The toxic effects of CA and DCF on thyroid hormones (THs) such as thyroid stimulating hormone (TSH), thyroxine (T4) and triiodothyronine (T3) levels were evaluated. During the short and long-term exposure period TSH level was found to be decreased at all concentrations of CA (except at the end of 14(th) day in 1 and 10µgL(-l) and 21(st) day in 1µgL(-l)) whereas in DCF exposed fish TSH level was found to be increased when compared to control groups. T4 level was found to be decreased at 1 and 100µgL(-l) of CA exposure at the end of 96h. However, T4 level was decreased at all concentrations of CA and DCF during long-term (35 days) exposure period. Fish exposed to all concentrations of CA and DCF had lower level of T3 in both the treatments. These results suggest that both CA and DCF drugs induced significant changes (P<0.01 and P<0.05) on thyroid hormonal levels of C. mrigala. The alterations of these hormonal levels can be used as potential biomarkers in monitoring of pharmaceutical drugs in aquatic organisms.

Clofibric acid induces hepatic CYP 2B1/2 via constitutive androstane receptor not via peroxisome proliferator activated receptor alpha in rat.

Peroxisome proliferator activated receptor α (PPARα) ligands, fibrates used to control hyperlipidemia. We demonstrated CYP2B induction by clofibric acid (CFA) however, the mechanism was not clear. In this study, HepG2 cells transfected with expression plasmid of mouse constitutive androstane receptor (CAR) or PPARα were treated with CFA, phenobarbital (PB) or TCPOBOP. Luciferase assays showed that CFA increased CYP2B1 transcription to the same level as PB, or TCPOBOP in HepG2 transfected with mouse CAR But failed to induce it in PPARα transfected cells. CYP2B expressions were increased with PB or CFA in Wistar female rats (having normal levels of CAR) but not in Wistar Kyoto female rats (having low levels of CAR). The induction of CYP2B by PB or CFA was comparable to nuclear CAR levels. CAR nuclear translocation was induced by CFA in both rat strains. This indicates that fibrates can activate CAR and that fibrates-insulin sensitization effect may occur through CAR, while hypolipidemic effect may operate through PPARα.

Synthesis, characterization, and preclinical evaluation of new thiazolidin-4-ones substituted with p-chlorophenoxy acetic acid and clofibric acid against insulin resistance and metabolic disorder.

We synthesized twenty thiazolidin-4-one derivatives, which were then characterized by standard chromatographic and spectroscopic methods. From the in vitro glucose uptake assay, two compounds behaved as insulin sensitizers, where they enhanced glucose uptake in isolated rat diaphragm. In high-carbohydrate diet-induced insulin resistant mice, these two thiazolidin-4-ones attenuated hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and glucose intolerance. They raised the plasma leptin but did not reverse the diabetes-induced hypoadiponectinemia. Additionally, compound 3a reduced adiposity. The test compounds were also able to reverse the disturbed liver antioxidant milieu. To conclude, these two novel thiazolidin-4-ones modulated multiple mechanisms involved in metabolic disorders, reversing insulin resistance and thus preventing the development of type-2 diabetes.

Conservative treatment of L-asparaginase-associated lipid abnormalities in children with acute lymphoblastic leukemia.

OBJECTIVE: To determine the incidence and clinical consequences of asparaginase-associated lipid abnormalities in children with acute lymphoblastic leukemia (ALL). METHODS: Sixty-five newly diagnosed children and adolescents aged 0.4-21 years with ALL or lymphoblastic lymphoma were retrospectively evaluated for lipid abnormalities. They were treated according to the ALLIC-BFM 2002 protocol between 2002 and 2005. Fasting cholesterol levels were measured in all patients and triglycerides (TG) in 42/65 patients. RESULTS: Prior to treatment, mean cholesterol level was 149 +/- 50 mg/dl, and increased to maximal level 274 +/- 124 mg/dl during treatment. Mean TG level during treatment was 459 +/- 526 mg/dl (range 54-3,009). Twelve patients (28%) had TG levels <200 mg/dl, 18 (43%) had 200-400 mg/dl, 3 (7%) had 400-600 mg/dl, 4 (10%) between 600 and 1,000 mg/dl, and 5 (12%) patients had >1,000 mg/dl. No association was found between TG levels and age or gender. One of the 12 patients with TG >400 mg/dl developed left saggital sinus thrombosis and left frontal lobe infarct. TG level at the time of the event was 2,640 mg/dl. None of the five patients with TG levels >1,000 mg/dl developed pancreatitis. Children with TG levels between 400 and 600 mg/dl were treated by fasting. Fibrates and heparin were added to those with levels >600 mg/dl. Lipid abnormalities normalized in all children upon completion of asparaginase treatment. CONCLUSIONS: Abnormalities of lipid profile in children with ALL during asparaginase therapy are relatively common. We recommend measuring TG before and during asparaginase treatment. Initiation of conservative treatment could prevent further increase of TG and decrease the risk of potential complications.

Effect of fibrates on lipid profiles and cardiovascular outcomes: a systematic review.

OBJECTIVE: Fibrates might represent a viable treatment option for patients who do not meet their target low-density lipoprotein levels on statins or who are resistant or intolerant to statins. New data from fibrate trials can be synthesized with the existing literature to better estimate their effects. METHODS: We systematically searched the literature to identify randomized, double-blind, placebo-controlled trials examining the effect of fibrates on lipid profiles or cardiovascular outcomes. We estimated the effect of fibrates on the incidence of nonfatal myocardial infarction and all-cause mortality using random effects models. RESULTS: Compared with placebo, fibrates were associated with greater reductions in total cholesterol (range: -101.3 mg/dL to -5.0 mg/dL) and triglycerides (range: -321.3 mg/dL to -20.8 mg/dL), and a greater increase in high-density lipoprotein (range: +1.1 mg/dL to +17.9 mg/dL) in all trials. Fibrates tended to be associated with a greater reduction in low-density lipoprotein (range: -76.3 mg/dL to +38.7 mg/dL) than placebo, although these results were not consistent across all trials. Fibrates were more efficacious than placebo at preventing nonfatal myocardial infarction (odds ratio=0.78; 95% confidence interval, 0.69-0.89), but not all-cause mortality (odds ratio=1.05; 95% confidence interval, 0.95-1.15). CONCLUSION: In addition to improving lipid profiles, fibrates are associated with an important decrease in nonfatal myocardial infarction, but do not substantially affect all-cause mortality. Potential applications include treatment for patients with statin resistance or isolated hypertriglyceridemia, or as an adjunct to other lipid-lowering therapies.

[Efficacy and safety of etofibrate in patients with non-proliferative diabetic retinopathy]. / Wirksamkeit und Sicherheit von Etofibrat bei Patienten mit nicht proliferativer diabetischer Retinopathie.

INTRODUCTION: Diabetic retinopathy is the leading cause of vision loss or blindeness in working-age adults in the developed and developing countries. No curative treatments are available for diabetic retinopathy and the most common symptomatic treatment, laser photocoagulation, provides only partial and temporary relief from the progressive vascular damage caused by this disease. Etofibrate (Lipo-Merz) is an orally-administered treatment for lipid disorders that combines fibrate and nicotinic acid in a slow-release formulation. PATIENTS AND METHODS: This report describes the results of a double-blind, randomised, placebo-controlled study, performed to evaluate the efficacy and safety of etofibrat in patients with type 2 diabetes mellitus and concomitant diabetic retinopathy. They received either placebo or 1000 mg/day etofibrate for up to 12 months. Efficacy analyses were based on visual acuity assessment and blinded expert ratings of ocular fundus pathology, as well as laboratory analyses of serum lipid parameters. RESULTS: The evaluable population comprised 296 patients, 148 in each treatment group, of whom 89% completed the study and 73% completed according to protocol. After 12 months of treatment, a significantly larger population of etofibrate-treated patients than placebo-treated patients showed improvements in ocular pathology (46% versus 32%, respectively, p < 0.001); similar findings were already apparent after 6 months of treatment (43% versus 31%, respectively p < 0.001). Etofibrate treatment also produced significant improvements in total cholesterol, LDL-cholesterol and HDL-cholesterol in comparison to the placebo treatment group. Safety evaluations (adverse events, laboratory parameters) did not reveal any clinically significant adverse effects of etofibrate in comparison to placebo. CONCLUSION: Etofibrate provides a safe and effective treatment for ocular pathology resulting from type 2 diabetes mellitus.

Niacin and fibrate use among patients with high triglycerides and low high-density lipoprotein cholesterol.

BACKGROUND: National guidelines recommend treating low HDL and/or high triglycerides (TG) with adjunctive therapy that supplements statin monotherapy in patients with multiple cardiovascular disease (CVD) risk factors. Niacin and fibrates have been shown in clinical trials to be effective as adjunctive therapy for these lipid abnormalities. OBJECTIVE: To evaluate the pharmacologic treatment of low HDL and high TG in real-world practice by assessing a large managed-care population with CVD risk factors enrolled in a commercial health plan. RESEARCH DESIGN AND METHODS: Complete lipid panel results (LDL, HDL, TG) obtained between 1/1/2006 and 12/31/2006 (index lab) were available for all participants. Subjects were observed 180 days pre-index to determine which CVD risk factors were present (male aged 45+, female 55+, coronary heart disease, hypertension, diabetes mellitus). Patients whose LDL was at goal but who had low HDL and high TG were assessed for lipid treatment status by evaluating outpatient pharmacy claims 6 months pre- and post-index. RESULTS: Treatment with any lipid therapy increased for all risk groups, and by total risk factors, from pre-index to post-index. Use of fibrates and niacin, alone or in combination with a statin, also increased for all risk groups, and by total risk factors as well, but was below expectations based on guideline recommendations. For example, among patients with 4 risk factors, <20% of patients with low HDL/high TG received niacin and/or a fibrate post-index date. CONCLUSIONS: Our results indicate that in actual clinical practice, niacin and fibrates are underutilized in the treatment of low HDL and high TG. The findings of this study must be considered within the limitations of database analysis as claims data are collected for the purpose of payment and not research.

Etofibrate enhances 123I-LDL-binding in human liver.

Etofibrate, a combination of fibric and nicotinic acid, is successfully used for the treatment of type IIb and IV hyperlipidemia. While an up-regulation of specific low density lipoproteins (LDL) binding sites in human platelets has been demonstrated, action on LDL-binding to the liver in patients and kinetic studies rare. This study aimed to investigate the influence of twice 500mg etofibrate daily given for 6 weeks on the in vivo binding of autologous LDL to the liver in 11 patients, 6 males, 5 females; aged 37-57 years, suffering from mixed hyperlipidemia. Etofibrate enhanced in vivo liver uptake of (123)I-LDL by 16.1% at mean, shortened plasma decay of LDL and improved lipid profile: serum total cholesterol was lowered by 14.9%, LDL-cholesterol was lowered by 22.2% and high-density lipoprotein (HDL)- cholesterol was increased by 10.9%. These findings are documenting a beneficial effect of the drug at the LDL liver receptor level in vivo.

Switching fibrate to statin in type 2 diabetic patients: consequences on lipid profile.

UNLABELLED: Interest of statins in terms of morbid-mortality reduction in primary and secondary prevention in type 2 diabetic patients has broadly been proven in recent studies, while evidence for fibrates preventive effect is considerably weaker. HMGCoA reductase inhibitors are known to decrease low density lipoprotein cholesterol (LDL C) in a greater extension than triglycerides (TG). In type 2 diabetic patients, the dyslipidemic profile is commonly associated with reduced high-density lipoproteins (HDL C), increased TG and normal or mildly elevated LDL C. PATIENTS AND METHODS: Type 2 diabetic outpatients (n=45) treated with fibrate with or without history of cardiovascular disease were included. Mean age was 57.7+/-13.2 yr, sex ratio was 16/39 (F/M), and BMI was 29.3+/-4.4 kg/m(2). Non-inclusion criteria were TG>or=3.5 g/L and intolerance to statins or a combined lowering lipid therapy. Serum lipid profile, HbA(1c) and creatin kinase (CK) were assessed under treatment with fibrate, then after a 3-month wash-out period, and after a 6-month treatment with a low dose of atorvastatin (10 mg/day). RESULTS: After a 3-month wash-out period, total cholesterol (TC) was 1.98+/-0.31 g/L (m+/-SD), TG 1.63+/-1.09 g/L, HDL C 0.46+/-0.12 g/L, and LDL C 1.22+/-0.31 g/L. Comparing lipid profile with atorvastatin vs fibrate, we observed a significant decrease in TC and LDL C (1.56 vs 1.79 g/L P=0.001, and 0.84 vs 1.09 g/L, P=0.001, respectively). No significant difference between treatments was observed for TG (1.35 vs 1.17 g/L, P=0.06), and HDL C (0.44 vs 0.48 g/L, P=0.15). When treated with atorvastatin, 90% of patients achieved a LDL C<1 g/L, compared to 51% when treated with fibrate (P=0.001). HbA(1c) remained about 7.6+/-1.5%, and CK in the normal range. CONCLUSION: In well-controlled type 2 diabetic patients previously treated with fibrate, short-term (6 months) treatment with low-dose atorvastatin (10 mg/day) improves TC and LDL C levels, without any alteration in TG and HDL C levels.

Plasma PCSK9 levels are significantly modified by statins and fibrates in humans.

BACKGROUND: Proprotein convertase subtilisin kexin-like 9 (PCSK9) is a secreted glycoprotein that is transcriptionally regulated by cholesterol status. It modulates levels of circulating low density lipoprotein cholesterol (LDLC) by negatively regulating low density lipoprotein receptor (LDLR) levels. PCSK9 variants that result in 'gain of function' have been linked to autosomal dominant hypercholesterolemia, while significant protection from coronary artery disease has been documented in individuals who carry 'loss of function' PCSK9 variants. PCSK9 circulates in human plasma, and we previously reported that plasma PCSK9 is positively correlated with total cholesterol and LDLC in men. RESULTS: Herein, we report the effects of two lipid-modulating therapies, namely statins and fibrates, on PCSK9 plasma levels in human subjects. We also document their effects on endogenous PCSK9 and LDLR expression in a human hepatocyte cell line, HepG2, using immunoprecipitation and immunoblot analyses. Changes in plasma PCSK9 following fenofibrate or gemfibrozil treatments (fibric acid derivatives) were inversely correlated with changes in LDLC levels (r = -0.558, p = 0.013). Atorvastatin administration (HMGCoA reductase inhibitor) significantly increased plasma PCSK9 (7.40%, p = 0.033) and these changes were inversely correlated with changes in LDLC levels (r = -0.393, p = 0.012). Immunoblot analyses of endogenous PCSK9 and LDLR expression by HepG2 cells in response to statins and fibrates showed that LDLR is more upregulated than PCSK9 by simvastatin (2.6x vs 1.5x, respectively at 10 muM), while fenofibrate did not induce changes in either. CONCLUSION: These results suggest that in vivo (1) statins directly increase PCSK9 expression while (2) fibrates affect PCSK9 expression indirectly through its modulation of cholesterol levels and (3) that these therapies could be improved by combination with a PCSK9 inhibitor, constituting a novel hypercholesterolemic therapy, since PCSK9 was significantly upregulated by both treatments.

Efficacy of rosuvastatin (5 mg and 10 mg) twice a week in patients intolerant to daily statins.

The aim of this study was to evaluate the efficacy of rosuvastatin twice weekly in 40 patients intolerant to daily statins. Rosuvastatin twice weekly alone or added to other lipid-lowering medications decreased total cholesterol by 19%, low-density lipoprotein cholesterol by 26%, and triglycerides by 14% (p<0.01 for all). High-density lipoprotein cholesterol did not change. Eight of the 40 patients (20%) discontinued twice-weekly rosuvastatin treatment because of muscle-related symptoms, during an average of 8 weeks of treatment. In conclusion, rosuvastatin twice weekly reduced total cholesterol, low-density lipoprotein cholesterol, and triglycerides and was well tolerated, but determining long-term tolerability requires more prolonged treatment.

[Effectiveness of cardiometabolic risk reduction in patients with type 1 diabetes mellitus]. / A kardiometabolikus kockázati tényezôk kezelésének eredményessége 1-es típusú diabetesben szenvedôk körében.

UNLABELLED: The attainment and maintenance of therapeutic goal of cardiovascular risk factors are of great clinical importance. The effectiveness of cardiovascular risk management is not well characterized during regular care of patients with type 1 diabetes mellitus. AIM: The aim of the study was to estimate the effectiveness of cardiovascular risk management in type 1 diabetic patients. METHODS: Adult patients with type 1 diabetes mellitus (n = 533; 256 men, 277 women; age: 35.6 +/- 11.6 years; duration of diabetes: 18.0 +/- 11.1 years; x +/- SD) were consecutively enrolled from 11 diabetes outpatient departments. Data on medical history, actual treatment, anthropometric and laboratory parameters as well as actual blood pressure were registered, while eating and smoking habits, education level and physical activity were evaluated by standardized questionnaires. The treating goal was set according to the national guideline which corresponds to the current international task force. RESULTS: Of 533 patients, the body mass index target level (< 25 kg/m 2 ) was achieved by 295 (55.5%) patients. Ideal waist circumference (< 80 cm for women and < 94 cm for men) was measured in 140 (50.5%) and in 165 (63.7%) patients, respectively. Optimal glycaemic control (HbA 1c level < 6.5%) was documented in 45 (8.4%) patients. Lipid lowering drugs (statins, fibrates or ezetimibe) were used by 130 patients, among which 53.1% reached the target triglyceride level, 71.5% the target HDL-cholesterol and 27.8% the target LDL-cholesterol levels. Taking the lipid target values together, only 23 (17.7%) patients were at goal. Antihypertensive drugs were used by 173 patients among which 29.5% reached the systolic and 34.8% the diastolic target values (< 130/80 mmHg). Regarding smoking habits, 94 (17.7%) patients were current smokers and 102 (19.2%) ex-smokers. CONCLUSIONS: The attainment of therapeutic goal of cardiovascular risk factors proved to be difficult in a substantial part of patients. Further efforts are needed for attaining and maintaining the established goal of cardiovascular risk management during regular care of adult patients with type 1 diabetes mellitus.

Colchicine: serious interactions.

(1) Renal failure, either pre-existing or induced by a nephrotoxic drug, increases the risk of adverse effects in patients taking colchicine; (2) Combining colchicines with a macrolide (except for spiramycin) carries a risk of life-threatening pancytopenia; (3) Ciclosporin co-administration can aggravate the neuromuscular adverse effects of colchicine; (4) Combining colchicine with lipid-lowering drugs (statins and fibrates) can cause myopathy; (5) Several mechanisms have been implicated: competition for cytochrome P450 or P-glycoprotein, additive adverse effects (especially on muscle), and colchicine accumulation due to a reduction in its renal excretion; (6) Patients with gout should use colchicine only after failure of symptomatic treatment: ice application, paracetamol, and possibly ibuprofen, a nonsteroidal antiinflammatory drug with well-documented adverse effects; (7) If colchicine is nevertheless used, it should be at the minimum effective dose. Close clinical monitoring is required in order to detect early signs of adverse effects, especially diarrhoea, the earliest sign in patients with renal failure and in the elderly.

High incidence of reduced plasma HDL cholesterol in diabetic patients treated with rosiglitazone and fibrate.

BACKGROUND: A paradoxical plasma HDL-Cholesterol (HDL-C) reducing effect following combined fibrate and thiazolidinediones (TZDs) therapy was recently reported in occasional cases. As HDL-C level is inversely related to cardiovascular disease (CVD) risk, we have studied the incidence of reduced HDL-C level following mono- and combined therapy with these drugs in a large diabetic population. METHODS: This study was designed as a retrospective 5-year study. Lipid profile records of 54 000 diabetic patients were searched for transient reduction of HDL-C to levels lower than 17 mg/dL, which was correlated with fibrates and/or TZD treatment. RESULTS: Transient reduction in plasma HDL-C to values lower than 17 mg/dL was observed in 0.02% (2/11 175) of the patients treated with fibrates alone, none of the rosiglitazone-treated patients (0/3213) and in 1.39% (9/649) of patients treated with combination of fibrate and TZD. HDL-C lowering effect was reversible upon stopping either fibrate or rosiglitazone and in some patients it occurred within 2 weeks. In two of the patients, the effect was dose-dependent. CONCLUSION: Severe reduction in plasma HDL-C is not rare when TZD and fibrates are co-administrated to diabetic hyperlipidemic patients. As low plasma HDL cholesterol is a risk factor for CVD, the physician should be alert to this phenomenon.

Stearoyl-CoA desaturase activity is elevated by the suppression of its degradation by clofibric acid in the liver of rats.

A mechanism by which fibrates control stearoyl-CoA desaturase (SCD) in the liver was studied. Treatment of rats with 2-(4-chlorophenoxy)-2-methylpropionic acid (clofibric acid) or feeding of a fat-free diet markedly elevated hepatic activity of SCD. Both the treatment with clofibric acid and the feeding of the fat-free diet caused an increase in the steady-state level of SCD1 mRNA and enhanced transcriptional rate. The half-lives of SCD for control rats, rats treated with clofibric acid rats, and rats fed the fat-free diet were estimated to be 2.0, 3.9, and 1.9 h, respectively. Activity of palmitoyl-CoA chain elongase (PCE) was increased by both clofibric acid treatment and feeding of the fat-free diet as was observed with SCD. Steady-state level of rat fatty acid elongase 2 mRNA was increased by the treatment with clofibric acid or feeding of fat-free diet, although the transcriptional rate was not altered. Different from SCD, PCE was highly stable and its half-life was not changed by either clofibric acid or fat-free diet. These results strongly suggest that the decreased degradation of SCD is responsible for the increase in its activity in addition to increased transcription of SCD1 in the rats treated with clofibric acid.

Clofibric acid, a peroxisome proliferator-activated receptor alpha ligand, inhibits growth of human ovarian cancer.

Recent reports have shown that peroxisome proliferator-activated receptor (PPAR)alpha ligands reduce growth of some types of malignant tumors and prevent carcinogenesis. In this study, we investigated the inhibitory effect of clofibric acid (CA), a ligand for PPARalpha on growth of ovarian malignancy, in in vivo and in vitro experiments using OVCAR-3 and DISS cells derived from human ovarian cancer and aimed to elucidate the molecular mechanism of its antitumor effect. CA treatment significantly suppressed the growth of OVCAR-3 tumors xenotransplanted s.c. and significantly prolonged the survival of mice with malignant ascites derived from DISS cells as compared with control. CA also dose-dependently inhibited cell proliferation of cultured cell lines. CA treatment increased the expression of carbonyl reductase (CR), which promotes the conversion of prostaglandin E(2) (PGE(2)) to PGF(2alpha), in implanted OVCAR-3 tumors as well as cultured cells. CA treatment decreased PGE(2) level as well as vascular endothelial growth factor (VEGF) amount in both of OVCAR-3-tumor and DISS-derived ascites. Reduced microvessel density and induced apoptosis were found in solid OVCAR-3 tumors treated by CA. Transfection of CR expression vector into mouse ovarian cancer cells showed significant reduction of PGE(2) level as well as VEGF expression. These results indicate that CA produces potent antitumor effects against ovarian cancer in conjunction with a reduction of angiogenesis and induction of apoptosis. We conclude that CA could be an effective agent in ovarian cancer and should be tested alone and in combination with other anticancer drugs.

[Analysis of dietary habits and dietary intake in hypertensive smokers]. / Ocena zwyczajów zywieniowych i sposobu zywienia osób palacych papierosy z nadcisnieniem tetniczym.

The aim of this study was to compare dietary habits and nutrient intake of hypertensive smokers with hypertensive non-smokers. The study population comprised 30 hypertensive smokers and 35 non-smokers, aged 30-60y. The participants were subjected to a triple 24-h diet recall and to a dietary habits questionnaire. The results showed that smokers had unhealthy patterns of nutrient intake. Smokers declared consuming too much fat, cholesterol and too low antioxidant vitamins, calcium and fibre. It was found that concentration of vitamin E in smokers' daily diet is significant lower than in non-smokers. Smokers consumed significantly higher saturated fatty acids comparing to non-smokers. In conclusion, smokers have unhealthy diet and it may intensify harmful effects of smoking in their organism.