Increased serum triglyceride clearance and elevated high-density lipoprotein 2 and 3 cholesterol during treatment of primary hypertriglyceridemia with bezafibrate

Background

Hypertriglyceridemia accompanied by low levels of high-density lipoprotein cholesterol (HDL-C) is a risk factor for coronary artery disease. High-density lipoprotein 2 (HDL₂) and 3 (HDL₃) are believed to suppress the progress of atherosclerosis through reverse cholesterol transport. As a result, peripheral tissues can be protected against excessive accumulation of cholesterol. Although bezafibrate is known to accelerate the increase of HDL-C, results are not standardized regarding increases of HDL₃ and HDL₂ subfractions.

Objective

This study assessed the effects of bezafibrate on serum triglyceride (TG) fractional clearance rate (K₂) and HDL₂ and HDL₃ cholesterol (HDL₂-C and HDL₃-C, respectively) levels in patients with primary hypertriglyceridemia (serum TG ≥150 mg/dL).

Methods

Outpatients with primary hypertriglyceridemia were enrolled in this 8-week study conducted at the Third Department of Internal Medicine, Nagoya City University Hospital (Nagoya, Japan). Oral bezafibrate was administered at a dose of 400 mg/d (200-mg tablet BID, morning and evening) for 8 weeks. After 8 weeks, serum levels of total cholesterol (TC), TG, HDL-C, HDL₂-C, and HDL₃-C were measured. A fat emulsion tolerance test to assess K₂ and measurements of plasma lipoprotein lipase (LPL) mass, LPL activity, and hepatic triglyceride lipase (HTGL) activity in postheparin plasma were performed before bezafibrate administration and after the course of treatment.

Results

Sixteen patients (10 men, 6 women; mean [SD] age, 54 [12] years [range, 30-69 years]; mean [SD] body mass index, 23 [2] kg/m²) entered the study. The following findings were observed in male and female patients after 8 weeks of treatment. A statistically significant reduction was observed in mean serum TG level (P<0.01). Significant increases were seen in HDL-C, HDL₂-C, and HDL₃-C (all P<0.01), K₂ (P<0.01), and in plasma LPL mass (P<0.01) and LPL activity (P<0.05). TC level and HTGL activity did not change significantly. No adverse effects related to the use of bezafibrate were documented.

Conclusions

In this study, bezafibrate treatment resulted in significant decreases in serum TG level and significant increases in HDL₂-C and HDL₃-C levels and plasma LPL mass and activity. We hypothesize that bezafibrate may increase HDL₃-C by promoting TG-rich lipoprotein catabolism and may increase HDL₂-C by promoting the conversion of HDL₃ to HDL₂.     

Allelic polymorphism -491A/T in apo E gene modulates the lipid-lowering response in combined hyperlipidemia treatment

BACKGROUND: Combined hyperlipidemia (CHL) is one of the dyslipidemias more frequently found in clinical practice, and lipid-lowering drugs are often necessary in its management. Some genetic loci have been associated with CHL expression, and some studies have shown modulation of drugs efficiency in the treatment of dyslipidemias by genetic polymorphisms. We have investigated whether common polymorphisms and mutations in the apolipoprotein (apo) E, lipoprotein lipase (LPL), and apo CIII genes influence atorvastatin or bezafibrate responses in patients with CHL. DESIGN: One hundred and sixteen subjects participating in the ATOMIX study (Atorvastatin in Mixed dyslipidemia) were randomized to treatment with either atorvastatin or bezafibrate. Apolipoprotein E genotype and common -491A/T and -219T/G polymorphisms in the apo E gene promoter region, Sst I polymorphism in the apo CIII gene (3238C/G), and D9N and N291S common mutations in the LPL gene were determined by polymerase chain reaction (PCR) and restriction enzyme digestion. RESULTS: Statistical analysis showed the influence of the -491A/T polymorphism in atorvastatin and bezafibrate treatments. Subjects carrying the -491T allele showed an increased LDL-cholesterol-lowering effect with atorvastatin compared with -491T allele noncarriers (-35% vs. -27%, P = 0.037). Subjects carrying the -491T allele, when on bezafibrate treatment, showed a lower triglyceride reduction compared with -491T allele noncarriers (-23% vs. -39%, P = 0.05). CONCLUSIONS: In our study, the -491A/T polymorphism in the apo E gene promoter region modulated the lipid-lowering efficiency of atorvastatin and bezafibrate in CHL patients. Such influence might explain some of the interindividual response variabilities observed for the two drugs, and could help in CHL management.     

Combined bezafibrate and medroxyprogesterone acetate have efficacy without haematological toxicity in elderly and relapsed acute myeloid leukaemia (AML)

Acute myeloid leukaemia (AML) causes life‐threatening deficits of functional blood cells that require management using red cell and platelet transfusion and aggressive treatment of neutropenic infections. Current cytotoxic chemotherapy further worsens the problem of reduced haemopoiesis and two‐thirds of patients are too frail to tolerate intensive chemotherapy at all. Median survival amongst these patients remains at <3 months emphasizing the urgent need for anti‐AML therapies that do not suppress haemopoiesis. Our laboratory studies showed combined Bezafibrate and Medroxyprogesterone acetate (BaP) had activity against AML without toxicity to normal stem cells. Here we report the safety and efficacy of BaP in 20 patients (19 AML, 1 high‐risk myelodysplasia) for whom intensive chemotherapy was not an option. No patient exhibited haematological toxicity from BaP. Eleven patients took BaP alone for >4 weeks. One reverted from high risk myelodysplasia and remains transfusion independent after 201 weeks of therapy. Three AML patients gained major haematological improvements for 22–30 weeks; in one, marrow was available to document a partial AML response. Thus, this trial indicates that BaP therapy has potential for treatment of elderly and relapsed AML.     

Short-term effect of bezafibrate on the expression of adiponectin mRNA in the adipose tissues: a study in spontaneously type 2 diabetic rats with visceral obesity

The effect of short-term bezafibrate (BF) administration over time on the expression of adiponectin mRNA in the tissues was examined in Otsuka Long Evans Tokushima Fatty (OLETF) rats. Eight-week-old rats were divided into the high-dose (100 mg/kg) BF group (n=15), the low-dose (10 mg/kg) BF group (n=15), or the control group (n=15) and followed up for 14 d. Triglyceride and free fatty acid levels significantly decreased in a dose-dependent manner in the high-dose BF group. The insulin levels increased with time, although they were significantly lower in the high-dose BF group on d 3 and 7 than the control group. Adiponectin levels significantly increased in the high-dose BF group. On d 14 of BF administration, the levels of VLDL and chylomicron were significantly lower in BF groups, and adiponectin mRNA expression in the white adipose tissue was significantly higher in the high-dose BF group. Findings from this study suggest that in type 2 diabetes with insulin resistance, hypertriglyceridemia is closely linked to adiponectin.     

苯扎贝特与阿西莫司治疗高脂血症的比较

目的 :观察苯扎贝特降低血脂的疗效。方法 :治疗组 4 1例 (男性 2 5例 ,女性 16例 ;年龄 64±s 8a)给苯扎贝特 0 .2 g ,po ,tid× 4wk。对照组 35例(男性 14例 ,女性 2 1例 ;年龄 61± 7a)给阿西莫司0 .2 5g ,po ,tid× 4wk。结果 :苯扎贝特降低血胆固醇 (TC)和三酰甘油 (TG)的总有效率为 84 %和88%。阿西莫司降低血TC和TG的总有效率为77%和 67%。 2药且均有升高高密度脂蛋白胆固醇、载脂蛋白AI/载脂蛋白B10 0 的作用 ,苯扎贝特降低TG的水平高于阿西莫司 (P <0 .0 5)。结论 :苯扎贝特是一个安全、有效的降脂药物 ,特别适用于高TG的治疗     

国产苯扎贝特治疗高脂血症

目的：观察国产苯扎贝特（Ｂｅｚ）对高脂血症的调脂疗效。方法：按随机、平行对照法半入选的５３例患者分为２组,Ａ组３３例,服国产Ｂｅｚ２００ｍｇ,ｔｉｄ。Ｂ组２０例,服进口Ｂｅｚ２００ｍｇ,ｔｉｄ。连续用８ｗｋ。结果：Ａ组治疗４ｗｋ,即可使ＴＣ降低７．１２％,ＴＧ降低３０．４７％,ＬＤＬ降低１５．４８％,ＴＣ／ＨＤＬ－Ｃ降低２２．８％,ＨＤＬ－Ｃ升高１４．２８％;８ｗｋ时更为显著,分别降低１２．４６％     

用加校正因子的主成分自身对照法测定苯扎贝特中杂质氯苯酪胺的含量

目的：建立加校正因子的主成分自身对照法测定苯扎贝特中杂质氯苯酪胺的含量。方法：通过方法学验证试验，证明所采用的高效液相色谱法外标法测定苯扎贝特中杂质氯苯酪胺的含量方法可行；再利用外标法，分别测定主成分苯扎贝特和杂质氯苯酪胺的保留时间，计算氯苯酪胺相对于苯扎贝特的相对保留时间，分别测定主成分苯扎贝特和杂质氯苯酪胺的线性方程，以斜率计算杂质氯苯酪胺相对于主成分苯扎贝特的校正因子；最终利用相对保留时间确定杂质氯苯酪胺的位置，用校正因子测定杂质氯苯酪胺的含量。结果：测得杂质氯苯酪胺相对于主成分苯扎贝特的相对保留时间为0．90，校正因子为1．2494。结论：用加校正因子的主成分自身对照法测定苯扎贝特中杂质氯苯酪胺的含量，方法可行。     

Comparison of the efficacy of simvastatin and standard fibrate therapy in the treatment of primary hypercholesterolemia and combined hyperlipidemia

Five multicenter, randomized, double-blind, placebo-controlled studies were conducted in France to compare the efficacy and safety of once-daily simvastatin treatment (10–40 mg/day) with conventional therapy with gemfibrozil 900 mg/day, ciprofibrate 100 mg/day, bezafibrate 400 mg/day, and fenofibrate 300 or 400 mg/day in a total of 800 patients with hypercholesterolemia. Simvastatin was associated with statistically significantly greater (p ? 0.01) mean percent reductions in plasma low-density lipoprotein (LDL) cholesterol compared with each of the five fibrate regimens, even when administered at its recommended starting dose of 10 mg/day. Furthermore, approximately 90% of patients treated once daily with simvastatin experienced an at least 20% decrease in plasma LDL cholesterol compared with only 36 to 68% of patients treated with the individual fibrate agents (p ? 0.05). The effectiveness of simvastatin in reducing LDL cholesterol did not differ as a function of the baseline plasma concentrations of total cholesterol or triglycerides. In contrast, the effectiveness of fibrate therapy in lowering plasma LDL cholesterol levels was significantly diminished (p ? 0.05) among patients with triglyceride concentrations > 1.7 mmol/1. Plasma highdensity lipoprotein (HDL) cholesterol levels were increased by approximately 10% after treatment with simvastatin or the fibrates. Although fibrate therapy was more effective overall in lowering plasma triglyceride levels, the effectiveness of simvastatin in reducing plasma triglyceride levels was generally 2- to 4-fold greater in patients with hypercholesterolemia associated with triglyceride levels ? 2.3 mmol/1 than in those with hypercholesterolemia associated with triglyceride levels < 2.3 mmol/1. The results of these studies confirm the superiority of simvastatin to standard fibrate therapy in reducing plasma levels of total and LDL cholesterol. They further indicate that once-daily treatment with simvastatin is effective in patients with isolated hypercholesterolemia or hypercholesterolemia associated with elevated triglyceride levels.     

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??Multiple acyl-CoA dehydrogenase deficiency??also known as glutaric aciduria type??is an autosomal recessive inherited metabolic disease. It is a mitochondrial electron transport chain and fatty acid metabolism disorder caused by a defect of electron transfer flavoprotein??ETF?? or ETF dehydrogenase??ETFDH????resulting in the damage to multiple organs such as myocardia??liver??brain and skeletal muscle. The clinical diagnosis of multiple acyl-CoA dehydrogenase deficiency is difficult due to the lack of specific symptoms and signs of the patients. To make a definitive diagnosis??blood aminoacids and acylcarnitine profiles??urinary organic acids profiles and gene analysis are necessary. According to the response to riboflavin??or vitamin B2????multiple acyl-CoA dehydrogenase deficiency could be divided into riboflavin-responsive form and riboflavin-unresponsive form. The riboflavin-responsive form is usually observed in the late-onset cases with good outcome. The patients of riboflavin-unresponsive form usually have early-onset with severe diseases. Bezafibrate, L-carnitine??coenzyme Q10??sodium-D??L-3-hydroxybutyrate and low-fat die should be considered for the treatment. Some patients with riboflavin-unresponsive form show poor outcome.     

苯扎贝特与菸酸肌醇脂对原发性高脂血症疗效观察

目的　观察苯扎贝特与菸酸肌醇脂的降脂疗效。方法　原发性高脂血症６６ 例，其中３４ 例（ 男性２０ 例，女性１４ 例，年龄５４ ±１２ 岁） 用苯扎贝特２００ｍｇ ．Ｐｏ．ｔｉｄ共治疗８ 周。另同病患者３２ 例（ 男性２２ 例，女性１０ 例，年龄５３ ±９ 岁） 用菸酸肌醇脂４００ｍｇ ．Ｐｏ ．ｔｉｄ 共治疗８ 周做为对照。结果　苯扎贝特组ＴＣ、ＴＧ、ＬＤＬ—ｃｈ 、ＡｐｏＢ、ＬＰ（ａ） 治疗２ 周后就有明显下降（ Ｐ ＜ ０ ．０１） ，ＨＤＬ—ｃｈ 、ＡｐｏＡ 明显上升（ Ｐ ＜ ０ ．０１） ，苯扎贝特药效明显强于菸酸肌醇脂，疗效随用药时间延长而提高，未见明显副作用。结论　苯扎贝特是一个安全有效的降脂药物，特别适用于多项脂质异常患者。