[Characteristics and Ecological Risk Assessment of Pharmaceutical Active Compounds in Guangdong Province].

Pharmaceutically active compounds(PhACs) have become a class of new pollutants in the environment after extensive production and use of PhACs in China. To investigate the pollution characteristics of PhACs in Guangdong Province, raw sewage was collected from 186 sewage treatment plants in 21 cities, including 178 townships and administrative districts in Guangdong Province. The pollution levels of ten typical PhACs in influent water of sewage treatment plants were analyzed using automatic solid phase extraction and high performance liquid chromatography-triple quadrupole mass spectrometry. The spatial distribution characteristics of PhACs in Guangdong Province were fully revealed, and the potential ecological risks of PhACs were evaluated. The results showed that PhACs were detected in all wastewater plants, and the mass concentration of PhACs ranged from 21.00 to 9558.25 ng·L-1. Metoprolo, acetaminophen, bezafibrate, and caffeine were the main pollutants. In terms of spatial distribution, the average mass concentration of ΣPhACs in various regions of Guangdong Province was in the following order:Pearl River Delta>North Guangdong>East Guangdong≈West Guangdong. When the mass concentration of ΣPhACs was over 2500 ng·L-1 in the influent water of sewage treatment plants, the concentration of PhACs in effluent was estimated according to the sewage disposal technology. The ecological risk of PhACs was carried out based on the effluent. The results revealed that the ecological risk of PhACs was low in Guangdong Province, and the risk of bezafibrate was moderate in the cities of Shaoguan, Jiangmen, and Shenzhen. The highest ecological risk of ΣPhACs was located in Shaoguan.

Whole body lipid oxidation during exercise is impaired with poor insulin sensitivity but not with obesity per se.

Equivocal findings regarding the influence of overweight/obesity on exercise lipid-oxidizing capacity (EX-LIPOX) might reflect inadequate control of 1) acute energy balance/macronutrient composition of diet; 2) intensity/duration of exercise; and/or 3) insulin sensitivity (IS) of participant. To assess independent/combined influences of IS and overweight/obesity with other factors controlled, we recruited sedentary adults with normal weight (NW; n = 15) or overweight/obesity (O; n = 15) subdivided into metabolically healthy (MH; n = 8) and unhealthy (MU; n = 7) groups (IS; MH > MU). Participants completed a 9-day, weight-stabilizing, controlled-feeding protocol comprising measurements of resting metabolism, body composition, oral glucose tolerance, and maximal exercise capacity. We measured EX-LIPOX during the initial 45 min of "steady state" during constant-work-rate cycling at 70% and 100% of participant gas-exchange threshold (GET). At 70%, average EX-LIPOX in absolute (0.11 ± 0.02 g·min-1) and relative (2.4 ± 0.3 mg·kgFFM-1·min-1) terms was lower for NW-MU than MH regardless of body composition (NW-MH, 0.19 ± 0.02 g·min-1/3.9 ± 0.3 mg·kgFFM-1·min-1; O-MH, 0.19 ± 0.02 g·min-1/3.7 ± 0.3 mg·kgFFM-1·min-1), whereas no difference was present for NW-MU and O-MU (0.15 ± 0.02 g·min-1/2.8 ± 0.3 mg·kgFFM-1·min-1). Multiple regression confirmed that with IS-controlled, overweight/obesity was not associated with decreased EX-LIPOX, whereas decreased EX-LIPOX was associated with decreased IS independent of overweight/obesity. Overweight/obesity also did not influence EX-LIPOX across MH groups or with cohort divided by body-composition classification alone (P > 0.05). Exercise lipid-oxidizing capacity is impaired with poor IS regardless of body composition, but not with overweight/obesity per se.NEW & NOTEWORTHY In this study, we have shown that the capacity to oxidize lipid during exercise is influenced by metabolic health of the exerciser regardless of body composition, but not by body composition per se. This observation refutes the belief that a reduced capacity to oxidize lipid is an obligatory characteristic of the overweight/obese condition while supporting the contention that exercise should be prescribed with specificity based on both absence/presence of overweight/obesity and compromise/lack thereof in metabolic health.

Occurrence of caffeine, fluoxetine, bezafibrate and levothyroxine in surface freshwater of São Paulo State (Brazil) and risk assessment for aquatic life protection.

The prioritization of active pharmaceutical ingredients (APIs) for monitoring programmes and/or environmental risk assessment (ERA) purposes is based on several criteria, including environmental occurrence data. However, data on API occurrence in Brazilian surface freshwaters are still scarce. The Brazilian Unified Health System (SUS) provides several medicines free-of-charge, including medications that have bezafibrate, fluoxetine and levothyroxine as the API. Thus, our objective was to investigate the occurrence of bezafibrate, fluoxetine and levothyroxine in samples collected at sampling sites included in the surface freshwater monitoring program of the São Paulo State Environmental Agency (CETESB); caffeine was also included in the analysis because it is commonly used as an anthropogenic marker of aquatic environment contamination. Monitoring results showed that levothyroxine was not found in any of the analysed samples. Caffeine was ubiquitous in the analysed samples, thus indicating anthropic contamination in the studied water bodies. Caffeine and bezafibrate presented risk quotient (RQ) < 1 for all the sampling sites and periods evaluated in this study. For fluoxetine, RQs > 1 were found in all water samples in which this API was found, indicating a potential risk for freshwater pelagic biota. Thus, fluoxetine should be regulated in São Paulo State in order to protect the aquatic biota. Additional occurrence studies in other Brazilian states are still needed to evaluate if fluoxetine is a nationwide pollutant.

Cardiovascular Health and Cognitive Decline 2 Decades Later in Men with Preexisting Coronary Artery Disease.

Cardiovascular health (CVH) factors are associated with lower risk of cardiovascular disease, stroke, and mortality. We investigated the association between a modified CVH metrics score and change in cognitive functions 2 decades later in patients with pre-existing coronary artery disease. A subset of 200 men (mean age at baseline 57.3 ± 6.3 years) who previously participated in a secondary prevention trial (1990 to 1997) underwent cognitive evaluation 14.6 ± 1.9 years after baseline (mean age 72.3 ± 6.2 years, T1 evaluation), and were re-evaluated for cognitive performance 19.9 ± 1.0 years after baseline (mean age 77.2 ± 6.4 years, T2 evaluation). A CVH metrics score at baseline was calculated, including 3 health parameters and 4 health behaviors. We have scored each of these CVH metrics into best (2 points), intermediate (1 point), and poor (0 points) levels. Cognitive function was assessed using the NeuroTrax Computerized Battery. A linear mixed model was used to assess change in cognitive functions between T1 and T2 cognitive evaluations. Among the 200 patients, 68 (34.0 %) had ≤7 (bottom group), 85 (42.5%) had 8 to 9 (middle group), and 47 (23.5%) had ≥10 (top group) CVH metrics points. After adjustments, the top group of CVH score versus others was associated with slower decline in the overall cognitive performance composite z-score (0.23 ± 0.09, p = 0.009) and on tests of executive and visual spatial functions (0.23 ± 0.11, p = 0.047, and 0.49 ± 0.17, p = 0.004, respectively). In conclusion, an inverse association was observed between the score of best CVH metrics and cognitive decline. Lifestyle factors are important predictors of late-life decline in cognitive function among high-risk patients.

Bezafibrate removal by means of ozonation: primary intermediates, kinetics, and toxicity assessment.

Bezafibrate (BZF) is a lipid regulator largely used for the treatment of hyperlipidaemia. As a result of its wide use, unmetabolized BZF is released in the environment with potential toxic effects for aquatic living organisms. The results obtained in this work show that ozonation is an efficient method to degrade BZF: after 10 min of treatment (corresponding to a dose of 0.73 mmol L(-1) of ozone), the complete BZF abatement is achieved, starting from an initial concentration of 0.5 mmol L(-1). However, only a small part of the substrate is mineralized. Two different experimental approaches (absolute and competition method) are adopted to estimate the second-order kinetic constants for the ozone attack at pH=6.0, 7.0 and 8.0. A good agreement was observed between the two kinetic methods adopted. The identification of main intermediates, attempted by high-performance liquid chromatograph (HPLC)-MS technique, indicates that the oxidation of BZF develops through both the hydroxylation of the aromatic ring and the attack of ozone on the unchlorinated aromatic one. The assessment of by-products biodegradability and acute toxicity demonstrates that ozonation is a suitable technique to improve the biodegradability and reduce the toxicity of waters containing BZF.

Um estudo de custo-eficácia com as abordagens nutricional e medicamentosa no tratamento da dislipidemia em pacientes HIV/AIDS / A cost-efficacy analysis with the nutritional and medical strategies for the treatment of dyslipidemia in HIV/AIDS patients

Esse estudo pretendeu fazer uma análise custo-eficácia de duas estratégias de tratamento de hiperlipidemia em pacientes HIV/AIDS, uma de caráter nutricional e a outra de caráter medicamentosa, mais precisamente com pravastatina e bezafibrato, respectivamente para casos de colesterol e triglicérides elevados, num horizonte entre 3 e 12 meses. Os dados foram coletados no CRT-AIDS de São Paulo. Encontram-se resultados similares em termos de eficácia no caso da hipercolesterolemia, a um custo menor via abordagem nutricional. As dosagens iniciais em ambos os grupos se revelaram similares. No caso da hipertrigliceridemia, verificou-se o mesmo efeito proporcional, apesar de que se deve considerar que as dosagens iniciais eram bastante diversas, apresentando os pacientes medicados níveis mais altos de triglicérides...

Pharmacoeconomic evaluation of anti-hyperlipidemic agent fenofibrate.

We evaluated the economic efficiency as well as the clinical effectiveness on serum lipid levels of a change in drug therapy from bezafibrate or a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor to fenofibrate. Subjects were 26 outpatients suffering from type IIb or type IV hyperlipidemia who visited our hospital between October 2000 and January 2001. Medication doses, and serum lipid levels were recorded prior to the change to fenofibrate and at 6 months after the change. Medical costs were also calculated at the same time points. A significant reduction in medical costs of 14.9% was observed following the change to fenofibrate. Serum lipid levels were not significantly different, although an increase in low density lipoprotein-cholesterol (LDL-cholesterol) was observed in patients changing from the HMG-CoA reductase inhibitor. The actual drug costs were reduced by 21.8% in the bezafibrate to fenofibrate group and by 23.7% in the HMG-CoA reductase inhibitor to fenofibrate group. Although the drug costs of changing to fenofibrate decreased significantly, other costs remained almost unchanged.

Statins in children: what do we know and what do we need to do?

Children have been tested and treated for hypercholesterolemia for more than 30 years. Although most treatment regimens have been limited to dietary intervention, statin use is increasing. Statins have been used in children since 1987, but published sources have only reported on small numbers of children with severe hypercholesterolemia. The available data indicates that statins can be useful and well tolerated. New data will be available in the next few years that will lead to the wider use of these drugs. Although statin drugs have proven to be safe in the adult population, physicians will be obliged to follow pediatric patients closely when these agents are widely used in the first few years. The use of highly effective safe drugs such as statins will allow for the assessment of the best time to initiate therapy in younger populations and what benefits may be found over the long term.

Bezafibrate increases prebeta 1-HDL at the expense of HDL2b in hypertriglyceridemia.

Prebeta1-high density lipoprotein (prebeta1-HDL), the initial acceptor of cell-derived cholesterol, can be generated from HDL(2) by hepatic lipase. Because bezafibrate elevates lipase activity, it may increase prebeta1-HDL at the expense of HDL(2). To answer this question, we determined the apolipoprotein A-I (apoA-I) distribution in 20 hypertriglyceridemics (triglycerides>2.26 mmol/L) and 20 sex-matched normolipidemics by native 2-dimensional gel electrophoresis. At baseline, prebeta1-HDL was 70% higher in hypertriglyceridemics than in normolipidemics (123.5+/-49.9 versus 72.5+/-34.1 mg/L apoA-I, P<0.01). Prebeta1-HDL was positively correlated with triglyceride (r=0.624, P<0.0001). A 4-week bezafibrate treatment (400 mg daily) increased prebeta1-HDL by 30% (160.2+/-64.5 mg/L apoA-I, P<0.05) but decreased HDL(2b) by 31% (from 188.8+/-94.9 to 129.3+/-78.7 mg/L apoA-I, P<0.05). Hepatic lipase activity increased by 24% (P<0.005). Prebeta1-HDL was generated either from ultracentrifugally isolated HDL(2) or from plasma during incubation with triglyceride lipase. In conclusion, bezafibrate increases prebeta1-HDL at the expense of HDL(2). We speculate that such an effect might partly contribute to the antiatherogenic action of bezafibrate.

Coagulofibrinolytic assessment of effects of bezafibrate on hypertriglyceridemia in postmenopausal women.

The present study investigates the effect of bezafibrate on lipid levels and coagulofibrinolytic factors. Subjects enrolled in the study included 124 postmenopausal women with hypertriglyceridemia. We examined the levels of tissue plasminogen activator (t-PA), plasminogen activator inhibitor type-1 (PAI-1), and blood coagulation factors VII and X as parameters of coagulofibrinolysis. After 12 weeks of bezafibrate therapy, mean serum triglyceride (TG) and remnant-like particle lipoprotein cholesterol (RLP-C) levels significantly decreased from baseline. Activated factor X levels decreased significantly by 11.3% (P < 0.01) and the ratio of tPA/PAI-1 (0.146+/-0.07) increased significantly by 37.7% from baseline (P < 0.05). The rates of change in activated factor VII and PAI-1 showed a significant positive correlate with the rates of change in TG and RLP-C (P = 0.001). These present findings suggest that bezafibrate improves triglyceride-rich lipoprotein metabolism and coagulofibrinolytic activity by increasing fibrinolysis in postmenopausal women with hypertriglyceridemia.

A head-to-head comparison of the cost effectiveness of HMG-CoA reductase inhibitors and fibrates in different types of primary hyperlipidemia.

The objective of this study was to compare the lifetime cost-effectiveness of HMG-CoA reductase inhibitors and fibrates for the treatment of hyperlipidemia. Estimates of lipid modification achieved due to drug therapy were based on published head-to-head comparisons of specific HMG-CoA reductase inhibitors and fibrates in randomized, double-blind studies. We used a validated coronary heart disease (CHD) prevention computer model to estimate the costs and benefits of lifelong lipid modification. The patients were middle-aged men and women who were free of CHD, with either primary type IIa or IIb hyperlipidemia. The intervention used were specific HMG-CoA reductase inhibitors and fibrates at several dosages, which reduced total cholesterol 11-34% and increased high-density lipoprotein cholesterol 1-29%. The main outcome measure was the cost per year of life saved after discounting benefits and costs by 5% annually. The lifetime cost effectiveness of HMG-CoA reductase inhibitors (fluvastatin, lovastatin, pravastatin, simvastatin) and fibrates (bezafibrate, fenofibrate, gemfibrozil) for the treatment of primary hyperlipidemia varied according to patient population, the effectiveness of each drug in modifying lipid levels, and the price of each drug. The estimates of cost per year of life saved for HMG-CoA reductase inhibitors range from $19,886 to $73,632, and $16,955 to $59,488 for fibrates according to gender and type of primary hyperlipidemia. Fluvastatin 20 mg/day was significantly more cost effective than gemfibrozil 1200 mg/day for male patients with type IIa hyperlipidemia. Simvastatin 17.3 mg/day or 20 mg/day yielded similar cost-effectiveness ratios compared with fibrates among type II hyperlipidemic patients. However, micronized fenofibrate was more cost effective than simvastatin 20 mg/day among type IIb patients. The cost effectiveness of lipid therapy varies widely and can be maximized by selecting specific drugs for specific lipid abnormalities.

Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients.

BACKGROUND: Bezafibrate has effects on lipid metabolism and haemostatic function. We undertook a double-blind, placebo-controlled intervention trial, the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT), to establish whether bezafibrate (200 mg three times daily) could retard or prevent the progression of atherosclerotic lesions in dyslipidaemic male survivors of myocardial infarction who were younger than 45 years at the time of the event. METHODS: 92 patients completed an initial 3-month period of dietary intervention and were randomly assigned to treatment with bezafibrate or placebo. Dietary intervention continued throughout the trial. Coronary angiography was done at baseline and after 2 and 5 years. 81 patients (42 bezafibrate treated and 39 placebo treated) who underwent baseline angiography and at least one post-treatment angiogram were included in the efficacy analysis. The primary endpoint was change in mean minimum lumen diameter. FINDINGS: The mean minimum lumen diameter decreased from baseline to the last angiographic assessment (2 or 5 years) by 0.06 mm (95% CI 0.15 reduction to 0.01 increase) in the bezafibrate group and by 0.17 mm (0.33 reduction to 0.09 increase) in the placebo group. The treatment effect was therefore 0.13 mm (95% CI 0.10 to 0.15; p=0.049). Parallel treatment effects, although not statistically significant, were observed for the secondary angiographic endpoints (mean segment diameter 0.02 mm [0.01-0.04] and percentage stenosis -3.41% [-4.00 to -2.98]). The cumulative coronary event rate was significantly lower among bezafibrate-treated than among placebo-treated patients (three vs 11 patients; p=0.02). There were significant treatment effects of bezafibrate for serum concentrations of cholesterol (-9%; p<0.001), very-low-density-lipoprotein (VLDL) cholesterol (-35%; p<0.001), serum triglycerides (-31%; p<0.001), VLDL triglycerides (-37%; p<0.001), and plasma fibrinogen (-12%; p=0.001), whereas low-density (LDL) cholesterol concentrations did not change. High density lipoprotein (HDL) cholesterol increased significantly with bezafibrate (9%; p=0.02). INTERPRETATION: The results show that bezfibrate improves dyslipidaemia, lowers plasma fibrinogen, slows the progression of focal coronary atherosclerosis, and reduces coronary events in young survivors of myocardial infarction.

Cost-effectiveness study of a lipid-lowering therapy in hyperlipoproteinaemia type IIb and type IV (Frederickson).

We performed a cost-effectiveness simulation of acipimox, bezafibrate, fenofibrate and gemfibrozil in patients with hyperlipoproteinaemia type IIb and IV (Frederickson). A distinction was made between patients with HLP type IIb and IV and HLP associated with diabetes mellitus type II (NIDDM). Direct costs were assessed as those incurred by social security for the treatment, and indirect costs were not taken into account. In appropriate dosages, all 4 substances can be considered equally efficacious in lowering lipid levels, although gallstones occur 3 times more frequently in patients treated with fibrates than in those treated with acipimox. Acquisition costs of the 4 drugs under consideration are comparable. Thus, when hospitalisation costs for treatment of gallstones are taken into account, therapy with acipimox is more cost effective than fibrate therapy.

Assessment of gastric antisecretory effects of phenoxyisobutyrate derivatives in the rat and the mouse.

After the observation of a low incidence of gastric carcinoid tumours in rats, but not in mice, given ciprofibrate for 2 years, ciprofibrate and related compounds were investigated for gastric antisecretory activity. A significant inhibition of gastric secretion, similar to that induced by comparable doses of cimetidine, was observed in the fischer rat 1.5 h after a single oral (200 or 500 mg kg-1) or intraduodenal (100 or 300 mg kg-1) administration of ciprofibrate, bezafibrate, and clofibric acid. Ciprofibrate had prolonged antisecretory activity when compared with bezafibrate or ranitidine. Prolonged inhibition of gastric secretion is proposed as the primary cause of gastric carcinoids in the rat, since in a comparative evaluation, antisecretory activity was observed in the rat but not in the mouse.