One-year study of the effect of bezafibrate on serum lipoprotein concentrations in hyperlipoproteinaemia.

The effect of bezafibrate (2-(4-[2-(4-chlorobenzamido)-ethyl]-phenoxy)-2-methylporopionic acid) (450 mg daily) on serum lipoprotein concentrations was studied for 1 year in 14 subjects with hyperlipoproteinaemia (3 of type II A, 2 of type II B, 2 of type III and 7 of type IV). After 2 months serum cholesterol decreased from 7.12--6.08 mmoles/l (15% P less than 0.01), triglycerides from 2.52--1.96 mmoles/l (22%, P less than 0.01), very low density lipoprotein triglycerides from 1.48--0.86 mmoles/l (42%, P less than 0.01) and low density lipoprotein cholesterol from 5.00--3.81 mmoles/l (24%, P less than 0.01). While triglyceride concentrations of serum and lipoproteins remained constant for 1 year, serum and LDL cholesterol concentrations increased slightly after 6 and 12 months. The former rise was partly due also to a rise of the possibly beneficial high density lipoprotein cholesterol from 1.27--1.68 mmoles/l (32%, P less than 0.01) after 6 months, making the effect on total cholesterol less pronounced. Subjective side-effects were nausea in one patient. No severe biochemical side-effects were noted.     

Influence of bezafibrate and colestipol on LDL-cholesterol, LDL-apolipoprotein B and HDL-cholesterol in hyperlipoproteinaemia

A significant increase of LDL-apolipoprotein B by 13% and LDL-cholesterol by 19% was observed in a group of 9 patients with hyperlipoproteinaemia Type III after bezafibrate treatment. Additional administration of colestipol caused a significant decrease of both LDL-apolipoprotein B by 18% and LDL-cholesterol by 25%. In 10 patients of hyperlipoproteinaemia Type IIb a significant decrease of both LDL-apolipoprotein B by 28% and LDL-apolipoprotein B by 18% was observed after bezafibrate therapy. When bezafibrate was given together with colestipol a further decrease of both LDL-cholesterol by 17% and LDL-apolipoprotein B by 16% occurred. HDL-cholesterol concentration increased significantly in both groups of hyperlipaemic patients during therapy. This may be the effect of both bezafibrate and colestipol. It is concluded that bile acid resins may effectively prevent the LDL-cholesterol concentration increase observed sometimes after clofibrate analogues.     

The fibrinolytic system and coagulation during bezafibrate treatment of hypertriglyceridemia

Bezafibrate was given to 23 hypertriglyceridemic but otherwise healthy middle-aged men in a double-blind, cross-over study to evaluate its effect on the components of the fibrinolytic system as well as on ATIII, FVIIIR: Ag, FVIII: C and platelet aggregation. Fibrinogen dropped markedly (P less than 0.05) and there was a small but significant fall of ATIII. The second wave of platelet aggregation was found much less frequently than in controls (P less than 0.001). Bezafibrate seemed to decrease the rate of formation of the first wave platelet aggregation.     

Effect of fish oil treatment on plasma lipoproteins in type III hyperlipoproteinaemia

Nine patients with type III hyperlipoproteinaemia and homozygosity for the apolipoprotein E2 isoform were treated with 15 g daily of MaxEPA, a fish oil preparation rich in eicosapentaenoic acid (2.7 g daily) and docosahexaenoic acid (1.8 g daily) for 16 weeks. Plasma lipoprotein and apolipoprotein concentrations were compared with those obtained during treatment with an olive oil preparation. MaxEPA treatment decreased plasma median total cholesterol, triglyceride and apolipoprotein B concentrations by 16, 53 and 19%, respectively. Plasma median very low density lipoprotein (VLDL)-cholesterol, triglyceride and apolipoprotein B concentrations were reduced by 45, 62 and 75% respectively, while the abnormal VLDL-cholesterol/triglyceride ratio remained unchanged. Individual reductions of VLDL concentrations varied considerably, for VLDL-cholesterol between 10 and 75%. In the majority of cases the abnormal late pre beta-bands on agarose electrophoresis, typical for type III hyperlipoproteinaemia normalized to pre beta-mobility on MaxEPA treatment. LDL-cholesterol and apolipoprotein B tended to increase after 8 weeks on MaxEPA but decreased again after 16 weeks. Median plasma high density lipoprotein cholesterol and apolipoprotein A-I did not change during MaxEPA treatment. It is concluded that MaxEPA have decreasing effects on plasma VLDL lipid and apolipoprotein concentrations in apolipoprotein E2 homozygous type III hyperlipoproteinaemia but that this effect is variable and unpredictable.     

Effect of bezafibrate treatment on the altered lipoprotein profiles in hypertriglyceridemic subjects

The effects of bezafibrate treatment on lipoprotein metabolism were investigated in hypertriglyceridemic subjects. Bezafibrate, a fibric acid derivative, was administered at 200-400 mg/day to 8 patients with hyperlipoproteinemia (type IIb and IV) for 3-6 months. We evaluated the effects of bezafibrate on the plasma levels of total cholesterol(chol), triglyceride(TG), and apoB. In addition, the lipid and apoB contents were also analyzed in VLDL, IDL, LDL and HDL fractions before and after the treatment. It was revealed that plasma levels of chol, TG and apoB significantly decreased after the treatment, 236.3 vs 210.9,192.4 vs 90.2 (p< 0.01) and 129.8 vs 116.2 (p<0.05) mg/dl respectively. VLDL-chol, VLDL-TG and VLDL-apoB dropped from 26.5,127.6 and 11.1 mg/dl to 9.1, 49.5 and 6.7 mg/dl respectively after the treatment. Regarding qualitative alterations of VLDL, TG/apoB, chol/apoB and TG + chol/apoB ratios in VLDL were significantly reduced, indicating that the size of VLDL was diminished by the treatment. In addition, HDL-chol increased from 40.4 to 60.8 mg/dl after the treatment. Consequently LDL-chol/HDL-chol significantly decreased. In conclusion, bezafibrate administration decreased the TG, chol and apoB content in VLDL, suggesting a reduced number of VLDL. Significant rise of HDL-chol and decrease of LDL-chol/HDL-chol are additional beneficial effects following bezafibrate treatment.     

降脂药物——必降脂对糖代谢的影响

目的　为探讨降脂药物———必降脂对糖代谢的影响。方法　将伴有高脂血症的７４ 例２ 型糖尿病患者随机分成２ 组，保持原糖尿病治疗方案不变。治疗组每天加服必降脂缓释片４００ ｍｇ ，对照组不加服。结果　３ 个月以后发现治疗组血胆固醇、甘油三酯， Ｌ Ｄ Ｌ Ｃ，空腹血糖有较明显下降， Ｈ Ｄ Ｌ Ｃ 轻度上升，糖耐量改善，胰岛素敏感指数上升。而对照组无显著变化。结论　必降脂除了能改善脂代谢紊乱以外还有助于纠正糖代谢异常。     

Postprandial concentrations and distribution of apo C-III in type 2 diabetic patients. Effect Of bezafibrate treatment

Apo C-III plays a key role in the metabolism of triglyceride-rich lipoproteins. It has recently been implicated as a potential determinant of the triglyceride (TG) lowering effect of fibrates, which down-regulate its expression. This hypothesis has been explored in ten moderately hypertriglyceridemic (TG 4.50+/-2.40 mmol/l) male type 2 diabetic patients tested with a lipid load before and after 4 weeks of treatment with 400 mg bezafibrate daily. Treatment lowered apo C-III concentrations by 20%, mainly in VLDL. Postprandially, apo C-III was transferred to chylomicrons in proportion to their TG content exclusively from HDL. VLDL retained their apo C-III and the apo C-III:TG ratio decreased as TG contents increased. At the end of the absorptive period (8 h) HDL did not recover the totality of their apo C-III (net loss 19 and 28% respectively before and after treatment, P<0.0001 for time effect). Bezafibrate lowered apo E by 33% (P<0.03). The apo C-III:apo E ratio did not vary significantly under treatment but underwent a postprandial decrease: 13% before and 18% (P=0.01) after treatment. These results indicate that repression of apo C-III expression and lowering of the apo C-III:E ratio are not likely mechanisms for the lipid-lowering effects of fibrates in type 2 diabetic patients. The potent effects on postprandial lipemia are suggestive of an apo C-III-independent stimulation of lipolysis.     

Effect of bezafibrate on lipoprotein secretion by cultured human hepatocytes

The secretion of newly synthesized very low density lipoprotein and low density lipoprotein (VLDL + LDL) and high density lipoprotein (HDL) in cultured human hepatocytes in the presence or absence of bezafibrate added to the culture medium has been evaluated. The content of triacylglycerol, apolipoprotein B, 3H-labeled proteins and 14C-labeled lipids accumulated in a culture medium increased linearly for periods up to 18 h. During incubation, cellular triacylglycerol content was unchanged. This hypolipidemic agent, at a concentration of 10 microM, inhibited secretion of the several VLDL + LDL [3H]apolipoproteins and the VLDL + LDL [14C]lipids, suggesting it can affect the processes of biosynthesis and secretion. The secretion of total [3H]apolipoproteins in the HDL fraction and [3H]protein (d greater than 1.21 g/ml) was unchanged after an exposure to bezafibrate (10 microM). Incubation in the presence of 10 microM bezafibrate resulted also in decreases in both total VLDL neutral lipids and apolipoprotein B secreted into the medium. These results indicate that bezafibrate might exert its plasma lipid-lowering effect by suppressing the VLDL production in liver and reducing the secretion of VLDL into the circulation.     

Mizoribine-induced rhabdomyolysis in a rheumatoid arthritis patient receiving bezafibrate treatment

Bezafibrate, one of fibric acid derivatives, is widely used to treat hypertriglyceridemia and diabetic dyslipidemia. Fibric acid derivatives are known to induce rhabdomyolysis as a side effect, especially when given to patients with renal dysfunction. Mizoribine, an imidazole nucleoside, is used as an immunosuppressive agent. Here, we present a case of a patient with rheumatoid arthritis who developed rhabdomyolysis while undergoing treatment with mizoribine concomitantly with bezafibrate. Drug-induced rhabdomyolysis was suspected and bezafibrate and mizoribine were discontinued, and the patient was treated with hydration. The patient's symptoms rapidly disappeared and abnormalities of blood and urine test findings also improved to normal levels within 1 week. When prescribing fibrates to patients with high risk of renal damage, caution should be exercised regarding interactions with other drugs and the potential for inducing rhabdomyolysis.     

Early determinants of overweight at 4.5 years in a population-based longitudinal study

OBJECTIVES: The roots of the obesity epidemic need to be traced back as early in life as possible in order to develop effective means for preventing obesity and its health consequences in the future. The aim of this paper is to examine a broad range of factors that may simultaneously contribute to childhood overweight in a population-based cohort of children followed from birth to 4.5 years, to determine which factors exert the most influence in early life. DESIGN: The analyses were performed using data from the Quebec Longitudinal Study of Child Development 1998-2002 (QLSCD). SUBJECTS: The study follows a representative sample (n=2103) of children born in 1998 in the Canadian province of Quebec. MEASURE: Measured height and weight were available for 1550 children aged 4.5 years. At 4.5 years, BMI was analyzed using the US CDC sex- and age-specific growth charts. In order to study children at their highest weights at various ages, odds ratios were presented for high birth weight, weight-for-stature at or above the 95th percentile at 5 months, and BMI at or above the 95th percentile at 4.5 years. Monthly weight gain between birth and five months has been analyzed. Children were also evaluated by the Z-score obtained from the standardized weight divided by height. Factors potentially related to children's weight include sex, gestational age and birth rank, breastfeeding, mothers' smoking status during pregnancy, family type at child's birth, and family income before pregnancy and when the children were 5 months and 4.5 years old. Other parental factors such as height and overweight/obesity (based on BMI) and other maternal factors (age, education, immigrant status) were also part of the analysis. RESULTS: Being in the highest quintiles of weight gain between birth and 5 months, as well as maternal smoking during pregnancy, almost double the odds of being overweight at 4.5 years. Parental overweight or obesity also increased the odds of being overweight at this age, as well as being raised in middle-income or in poor families. A greater proportion of children born to nonsmoking mothers with higher weights (more than 4000 g) were overweight at 4.5 years, the percentage being greatest for those in the highest weight-gain categories from birth to 5 months. The pattern was different for children born to smoking mothers. The greatest proportion of 4.5-year-old overweight children was seen for children born in the normal weight-range category (3000-4000 g) who were in the highest quintiles of weight gain from birth to 5 months, and for children with high birth weights (more than 4000 g) who were in the lowest quintiles of birth-to-5-months weight gain. Children who were overweight at 4.5 years and who had been born to smoking mothers started life with a birth weight around that for the population means, but they gained more weight in the first 5 months of life than did the children of nonsmoking mothers. CONCLUSION: This study indicates that behavioral and social factors exert critical influences on the onset of childhood overweight in preschool years. From a population-health perspective, interventions aimed at preventing childhood obesity would do well to target smoking pregnant women, as well as nonsmoking pregnant women at risk for giving birth to high-birth-weight children, paying particular attention to rapid weight gain in the first months of life.     

Low-fat diet versus low-carbohydrate diet in the treatment of type IV hyperlipoproteinaemia.

The response to dietary management was studied in 24 hypertriglyceridaemic out-patients. Fourteen patients were kept on a diet low in fat and cholesterol and high in polyunsaturated fatty acids; 10 of these patients subsequently followed a period of low-carbohydrate diet. At the end of the first period a significant decrease of serum triglyceride, cholesterol and beta-lipoproteins was observed; after the second feeding period no substantial change of serum lipoprotein pattern occurred. Ten patients were given a low-carbohydrate diet that produced a significant fall of the levels of triglycerides and pre-beta-lipoproteins. Six of these subjects continued the experiment with the low-fat diet; during this period a further trend toward reduction of serum triglyceride, cholesterol and beta-lipoproteins was observed which, however, was not statistically significant. We conclude that serum triglyceride levels can be lowered both by a low-carbohydrate diet and by a low-fat diet, but the latter has the advantage of also producing a significant fall of serum cholesterol and beta-lipoproteins.     

C ASE R EPORT: Occurrence of hepatocellular carcinoma 4.5 years after successful treatment with virus clearance for chronic hepatitis C

A 67-year-old man with hepatitis C virus infection and histological features of chronic active hepatitis was treated with human recombinant interferon alpha-2b. He responded successfully to interferon with normalization of serum alanine aminotransferase and continuous eradication of hepatitis C virus. However, 4.5 years after the end of interferon therapy, hepatocellular carcinoma, 20 mm in diameter, was detected by routine ultrasonographic screening. The patient underwent surgical treatment for resection of the hepatocellular carcinoma. The non-cancerous liver tissue was histologically normal. This suggests that patients who have shown a complete response to interferon therapy for chronic hepatitis C should be followed up closely.