Reductions In Apolipoprotein Research Articles

Effect of Combination Nicotinic Acid and Gemfibrozil Treatment on Intermediate Density Lipoprotein, and Subclasses of Low Density Lipoprotein and High Density Lipoprotein in Patients With Combined Hyperlipidemia

The goal of this study was to determine, using analytic ultracentrifugation, the effect of nicotinic acid alone or nicotinic acid added to gemfibrozil on lipoprotein subclass distribution, including intermediate-density lipoprotein (IDL; low-density to very low density flotation rate [S(f)] 12 to 20); low-density lipoprotein (LDL) subfractions LDL-I (S(f) 7 to 12), LDL-II (S(f) 5 to 7), LDL-III (S(f) 3 to 5), and LDL-IV (S(f) 0 to 3); and high-density lipoprotein (HDL) subfractions HDL(2) (high-density flotation rate 3.5 to 9.0) and HDL(3) (high-density flotation rate 0 to 3.5). Patients with combined hyperlipidemia were randomized to nicotinic acid (1,500 mg/day) plus placebo or nicotinic acid plus gemfibrozil (1,200 mg/d) for 12 weeks. Baseline characteristics were similar between the 2 groups, and mean LDL cholesterol (180 +/- 33 mg/dl) and triglycerides (310 +/- 126 mg/dl) were typical for patients with combined hyperlipidemia. Treatment with nicotinic acid resulted in a reduction in dense LDL (S(f) 5 to 7; p = 0.02), which was counterbalanced by an increase in buoyant LDL (S(f) 7 to 12; p = 0.03) that resulted in no significant LDL mass or LDL cholesterol change. IDL was reduced (p = 0.005) and HDL(2) increased by 143% (p = 0.004). The combination of nicotinic acid and gemfibrozil resulted in a further 17.8% reduction in apolipoprotein B (p = 0.06), a further 33.8% reduction in IDL (p = 0.06), and a greater reduction in the apolipoprotein B/apolipoprotein A-I ratio (p = 0.02). The combination of nicotinic acid and gemfibrozil reduced atherogenic by IDL 71%, dense LDL-III by 52%, and apolipoprotein B by 37% and increased protective HDL(2) by 90%. In conclusion, this investigation revealed that a combination of a fibric acid derivative and nicotinic acid offers greater improvement in detailed lipoprotein subclass distribution and apolipoprotein ratios than monotherapy.

Simvastatin improves flow-mediated dilation but reduces adiponectin levels and insulin sensitivity in hypercholesterolemic patients.

We hypothesized that simvastatin may reduce adiponectin levels and insulin sensitivity in hypercholesterolemic patients. This was a randomized, double-blind, placebo-controlled, parallel study. Age, sex, and BMI were matched. Thirty-two patients were given placebo, and 30, 32, 31, and 31 patients were given daily 10, 20, 40, and 80 mg simvastatin, respectively, during a 2-month treatment period. Simvastatin doses of 10, 20, 40, and 80 mg significantly reduced total cholesterol (mean changes 27, 25, 37, and 38%), LDL cholesterol (39, 38, 52, and 54%), and apolipoprotein B levels (24, 30, 36, and 42%) and improved flow-mediated dilation (FMD) (68, 40, 49, and 63%) after 2 months of therapy compared with baseline (P < 0.001 by paired t test) or compared with placebo (P < 0.001 by ANOVA). Simvastatin doses of 10, 20, 40, and 80 mg significantly decreased plasma adiponectin levels (4, 12, 5, and 10%) and insulin sensitivity (determined by the Quantitative Insulin-Sensitivity Check Index [QUICKI]) (5, 8, 6, and 6%) compared with baseline (P < 0.05 by paired t test) or compared with placebo (P = 0.011 for adiponectin and P = 0.034 for QUICKI by ANOVA). However, the magnitudes of these percent changes (FMD, adiponectin, and QUICKI) were not significantly different among four different doses of simvastatin despite dose-dependent changes in the reduction of apolipoprotein B levels. Simvastatin significantly improved endothelium-dependent dilation, but reduced adiponectin levels and insulin sensitivity in hypercholesterolemic patients independent of dose and the extent of apolipoprotein B reduction.

Potent Reduction of Apolipoprotein B and Low-Density Lipoprotein Cholesterol by Short-Term Administration of an Antisense Inhibitor of Apolipoprotein B

Potent Reduction of Apolipoprotein B and Low-Density Lipoprotein Cholesterol by Short-Term Administration of an Antisense Inhibitor of Apolipoprotein B

A carbohydrate restricted diet (CRD) favorably affects lipoprotein metabolism in overweight men

To determine the effects of a CRD with and without soluble fiber on lipoprotein metabolism, 29 men were matched by age and BMI then randomly assigned to consume 3 g/d of a soluble fiber supplement (n=14) or placebo (n=15) with a macronutrient distribution of ~10%, carbohydrate, 65% fat, and 25% protein for 12 wks. Lipoprotein particle size and quantity were measured by nuclear magnetic resonance. No between groups differences were observed in any parameter, thus data were pooled and compared from baseline to 12 wks. After 12 wks, subjects lost a mean 7.5 kg (P<0.001). Plasma LDL-C decreased by 8.9% and mean LDL particle size increased by 2.5% (P<0.001). Consistent with the hypothesized metabolic origins of LDL heterogeneity, greatest reductions were seen in large VLDL particles (−47−7%) leading to significant reductions in small LDL particles (−29.9%) and increases in large LDL particles (35.4%). The 38.6% reduction in plasma triglycerides (TG) was associated with significant reductions in apolipoprotein C-I (−13.8%), C-III (− 21.2%), and E (−12.5%). HDL-C increased by 12% (P<0.05), with increased mean HDL particle diameter and large HDL particle number (P<0.001). Changes in plasma TG positively correlated with reductions in large VLDL (P<0.01) and negatively correlated with large HDL (P<0.01). We conclude that a CRD alters the secretion and processing of plasma lipoproteins rendering VLDL, LDL and HDL particles associated with decreased risk for atherosclerosis and coronary heart disease.

The role of exercise in modulating the impact of an ultralow-fat diet on serum lipids and apolipoproteins in patients with or at risk for coronary artery disease

Ultralow-fat diets are known to reduce high-density lipoprotein cholesterol (HDL-C) levels. In the setting of a multicomponent lifestyle intervention program, relationships between exercise variables and HDL-C levels were examined to determine whether exercise moderates this dietary effect on serum lipids and apolipoproteins. We performed a 3-month, prospective, nonrandomized lifestyle intervention study (< or = 10% dietary fat; aerobic exercise [180 min/wk], group support, and yoga [60 min/day]) in 120 subjects with or at risk for coronary artery disease. After 3 months, dietary fat intake was reduced to 8.7% +/- 2.6% of total intake and the median weekly exercise time was 194 minutes. High-density lipoprotein cholesterol levels decreased by 8.3 +/- 11.3 mg/dL (P < .001), and triglyceride levels increased by 17.6 +/- 102.7 mg/dL (P = .026). A small dense low-density lipoprotein cholesterol (LDL-C) phenotype emerged indicated by a 13.8% LDL-C reduction accompanied by only a 2.3% reduction in apolipoprotein B levels (P = .064). Among subjects with exercise amounts less than those of the group median, HDL-C reductions were greater in those with more than (-13.5 +/- 16.0 mg/dL) versus less than (-2.5 +/- 7.5 mg/dL) the median reductions in fat intake (P = .026). Even among subjects who exercised > 194 min/wk, HDL-C was reduced compared with baseline (-7.4 +/- 7.9 mg/dL, P < .001). An ultralow-fat diet as a component of a comprehensive lifestyle intervention induces reductions in HDL-C and the emergence of a dyslipidemic lipid profile. Aerobic exercise only partially mitigates this effect.

Progestogens of varying androgenicity and cardiovascular risk factors in postmenopausal women receiving oestrogen replacement therapy

Medroxyprogesterone (MP) was used as the progestogen in randomized clinical trials of postmenopausal hormone replacement on cardiovascular risk. To attempt to understand the lack of benefit in these trials, we have examined the effects of MP and two other progestogens, the less androgenic desogestrel (DG) and the more androgenic norethisterone (NE), on cardiovascular risk factors against a background of oestrogen therapy. Thirty-four women were treated with conjugated equine oestrogens (CEE) 0.625 mg daily alone for 12 weeks, followed in random order by each of the three progestogens (DG 75 microg, MP 10 mg and NE 1 mg daily) given sequentially for three 12-week cycles while maintaining the same CEE treatment. We measured serum lipoproteins, paraoxonase activity, C-reactive protein (CRP), fibrinogen, fasting glucose and insulin levels at baseline, at the end of the oestrogen-only phase and at the end of each of the combined oestrogen and progestogen phases. The addition of progestogens to CEE maintained the oestrogen-induced reduction in apolipoprotein B (apo B) and lipoprotein (a) [Lp(a)], and further lowered total cholesterol (P < 0.01) and fibrinogen (P < 0.001). CEE raised serum triglyceride (P < 0.001) and CRP (P < 0.01) concentrations, which reverted towards pre-oestrogen levels with progestogens. Progestogens significantly reduced high density lipoprotein (HDL) cholesterol (P < 0.05). NE was associated with the greatest reduction in HDL cholesterol and apo A1, but was most effective in preserving paraoxonase activity and reducing the potentially unfavourable oestrogen-induced increases in triglycerides and CRP. Preconceptions that more androgenic progestogens necessarily have more unfavourable effects on cardiovascular risk factors may require revision.

Hepatic PTP-1B Expression Regulates the Assembly and Secretion of Apolipoprotein B–Containing Lipoproteins

Protein tyrosine phosphatase-1B (PTP-1B) plays an important role in regulation of insulin signal transduction, and modulation of PTP-1B expression seems to have a profound effect on insulin sensitivity and diet-induced weight gain. The molecular link between PTP-1B expression and metabolic dyslipidemia, a major complication of insulin resistance, was investigated in the present study using PTP-1B knockout mice as well as overexpression and suppression of PTP-1B. Chronic fructose feeding resulted in a significant increase in plasma VLDL in wild-type mice but not in PTP-1B knockout mice. Lipoprotein profile analysis of plasma from PTP-1B knockout mice revealed a significant reduction in apolipoprotein B (apoB100) lipoproteins, associated with reduced hepatic apoB100 secretion from isolated primary hepatocytes. In addition, treatment of cultured hepatoma cells with PTP-1B siRNA reduced PTP-1B mass by an average of 41% and was associated with a 53% decrease in secretion of metabolically labeled apoB100. Conversely, adenoviral-mediated overexpression of PTP-1B in HepG2 cells downregulated the phosphorylation of insulin receptor and insulin receptor substrate-1 and caused increases in cellular and secreted apoB100 as a result of increased intracellular apoB100 stability. Collectively, these findings suggest that PTP-1B expression level is a key determinant of hepatic lipoprotein secretion, and its overexpression in the liver can be sufficient to induce VLDL overproduction and the transition to a metabolic dyslipidemic state.

Elevation of plasma phospholipid transfer protein increases the risk of atherosclerosis despite lower apolipoprotein B-containing lipoproteins

Plasma phospholipid transfer protein (PLTP) transfers phospholipids between lipoproteins and mediates HDL conversion. PLTP-overexpressing mice have increased atherosclerosis. However, mice do not express cholesteryl ester transfer protein (CETP), which is involved in the same metabolic pathways as PLTP. Therefore, we studied atherosclerosis in heterozygous LDL receptor-deficient (LDLR(+/-)) mice expressing both human CETP and human PLTP. We used two transgenic lines with moderately and highly elevated plasma PLTP activity. In LDLR(+/-)/huCETPtg mice, cholesterol is present in both LDL and HDL. Both are decreased in LDLR(+/-)/huCETPtg/huPLTPtg mice (>50%). An atherogenic diet resulted in high levels of VLDL+LDL cholesterol. PLTP expression caused a strong PLTP dose-dependent decrease in VLDL and LDL cholesterol (-26% and -69%) and a decrease in HDL cholesterol (-70%). Surprisingly, atherosclerosis was increased in the two transgenic lines with moderately and highly elevated plasma PLTP activity (1.9-fold and 4.4-fold, respectively), indicating that the adverse effect of the reduction in plasma HDL outweighs the beneficial effect of the reduction in apolipoprotein B (apoB)-containing lipoproteins. The activities of the antiatherogenic enzymes paraoxonase and platelet-activating factor acetyl hydrolase were both PLTP dose-dependently reduced ( approximately -33% and -65%, respectively). We conclude that expression of PLTP in this animal model results in increased atherosclerosis in spite of reduced apoB-containing lipoproteins, by reduction of HDL and of HDL-associated antioxidant enzyme activities.

Effect of Aspirin Treatment on Serum Concentrations of Lipoprotein(a) in Patients with Atherosclerotic Diseases

Increased serum lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerosis. We previously reported that aspirin reduced Lp(a) production by cultured hepatocytes via the reduction of apolipoprotein(a) [apo(a)] gene transcription. We evaluated both the effect of aspirin treatment (81 mg/day) on serum Lp(a) concentrations and the correlation between the degree of reduction in serum Lp(a) and the type of apo(a) isoform in 70 patients with coronary artery disease or cerebral infarction. Aspirin lowered serum Lp(a) concentrations to approximately 80% of the baseline values in patients with high Lp(a) concentrations (>300 mg/L). The percentage of decrease in serum Lp(a) was larger in patients with high Lp(a) than in patients with low Lp(a) (<300 mg/L), irrespective of apo(a) isoform size. The decreases in serum Lp(a) in high Lp(a) patients with both the high-molecular-weight and the low-molecular-weight isoforms were positively correlated with the baseline Lp(a) concentrations. Because the secretory efficiencies of apo(a) in the same isoform are likely to be similar, the difference in serum Lp(a) concentrations in patients having the same apo(a) isoform depends on the transcriptional activity of the apo(a) gene. These findings suggest that aspirin decreases serum Lp(a) concentrations via a decrease in apo(a) gene transcription more effectively in patients with high transcriptional activity of this gene.

A novel TC deletion resulting in Pro 260→Stop in the human LCAT gene is associated with a dominant effect on HDL-cholesterol

Human lecithin:cholesterol acyltransferase (LCAT) plays a key role in the biogenesis of circulating high-density lipoprotein-cholesterol (HDL-C) and reverse cholesterol efflux. We investigated the molecular defect in the LCAT gene in a family with low levels of HDL-C. The proband, a 53-year-old woman from Oklahoma City, had a HDL-C level of 0.21 mmol/l. The LCAT activity in the proband was 5 nmol/ml/h and cholesterol esterification rate was 54.2 nmol/ml/h, consistent with LCAT deficiency. Analysis of polymerase chain reaction (PCR) amplified subgenomic fragments of LCAT DNA on polyacrylamide gels revealed heteroduplex bands in the proband and three other affected individuals in exon 6. DNA sequence analyses of the proband's LCAT gene identified a 2 base pair deletion (TC) (base pairs 4544–4545, corresponding to amino acid 255) in the heteroduplex allele, thereby converting Pro 260 to a premature stop codon and a predicted truncated protein of 260 amino acids. This is approximately 60% of the length of the normal translated protein. The heterozygous individuals also revealed significant reduction in apolipoprotein A-1 levels compared with the unaffected family members ( n=4). The marked reduction in HDL-C in the proband and sibling suggests a dominant effect of this mutation on HDL-C levels. Furthermore, because the deletion results in a heterozygous allele that can be detected by a simple PCR reaction and polyacrylamide gel-size fractionation, it may be possible to rapidly screen susceptible individuals for the presence of this mutation.

The efficacy of accumulated short bouts versus single daily bouts of brisk walking in improving aerobic fitness and blood lipid profiles

Fifty-six subjects (19 men and 37 woman) aged between 40 and 66 completed the study. They were allocated into three walking groups and a control group (C). The three walking groups performed the same total amount of walking for 18 weeks, but completed it in bouts of differing durations and frequencies. These were Long Walkers (LW; 20-40 min/bout), Intermediate Walkers (IW; 10-15 min/bout) and Short Walkers (SW; 5-10 min/bout); with the IW and SW performing more than one bout of walking a day. Following the 18 week walking programme, compared to the C group all walking groups showed similar improvements in fitness as determined by a reduction in blood lactate during a graded treadmill walking test (LW 1.0 mmol/l; IW 0. 8 mmol/l; SW 1.2 mmol/l; C 0.2 mmol/l; P = 0.003) and reduction in final heart rate (LW 8 beats/min; IW 6 beats/min; SW 10 beats/min; C 0 beats/min; P = 0.056). Also compared to the C group, the LW and IW groups recorded statistically significant decreases in low-density lipoprotein cholesterol (LW 0.29 mmol/l; IW 0.41 mmol/l; P = 0.024), whereas the control group showed a mean increase of 0.22 mmol/l. The LW and IW groups also showed significant reductions in apolipoprotein (apo) A-II (LW 0.05 g/l; IW 0.02 g/l; SW 0.01 g/l; C 0.00 g/l; P = 0.012) with the LW recording a statistically significant increase in the ratio of apo A-I/A-II (LW, 0.19, P = 0. 044). In conclusion, some health benefits were achieved from all walking programmes. However, whilst the changes in aerobic fitness were similar, the effects upon blood lipid profiles were not. The findings from this study suggest that the LW regimen was most effective in benefiting blood lipid profile, followed by the IW regimen, with the SW being least potent. Nevertheless, for the sedentary/low-active members of society, any improvement in health may be considered as important. Therefore accumulated bouts of moderate intensity exercise, which according to theories of exercise behaviour may be more easily incorporated into an individual's lifestyle than single prolonged bouts, may be advocated for health promotion but may not be as effective as the traditionally prescribed 20-40 min bouts.

Reduction in apolipoprotein-mediated removal of cellular lipids by immortalization of human fibroblasts and its reversion by cAMP: lack of effect with Tangier disease cells

High density lipoprotein (HDL) phospholipids and apolipoproteins remove cellular lipids by two distinct mechanisms, but their relative contribution to reverse cholesterol transport is unknown. Whereas phospholipid-mediated cholesterol efflux from cultured cells reflects the activity of the HDL receptor SR-BI, apolipoprotein-mediated lipid removal is regulated in response to changes in cellular cholesterol content (positive) and cell proliferation rates (negative). Here we show that immortalization of human skin fibroblast lines with the papillomavirus E6/E7 oncogenes increased their proliferation rates and selectively reduced the activity of the apolipoprotein-mediated lipid removal pathway. This reduction was accompanied by a decrease in cellular cAMP levels and was reversed by treatment with a cAMP analog. The stimulatory effect of cAMP was independent of changes in cellular phenotype or activities of cholesteryl ester cycle enzymes. The severely impaired apolipoprotein-mediated lipid removal pathway in Tangier disease fibroblasts, which persisted after immortalization, was not improved by treatment with a cAMP analog, implying that the cellular defect in Tangier disease is upstream from this cAMP-dependent signaling pathway.These results indicate that papillomavirus-induced immortalization of fibroblasts selectively reduces the activity of the apolipoprotein-mediated lipid removal pathway by a cAMP-dependent process, perhaps to prevent loss of cellular lipids needed for continual membrane synthesis.

The Water-Soluble Extract of Chicory Influences Serum and Liver Lipid Concentrations, Cecal Short-Chain Fatty Acid Concentrations and Fecal Lipid Excretion in Rats

Sprague-Dawley rats (n = 32) were fed diets without fiber (control) or containing 1 or 5% chicory extract or 5% inulin for 4 wk; 0.2% cholesterol was added to all diets. Rats fed chicory extract and inulin diets had significantly higher serum high density lipoprotein (HDL) cholesterol and generally lower low density lipoprotein (LDL) cholesterol concentrations, thus significantly greater ratios of HDL/LDL cholesterol compared with the controls (P < 0.05). The serum apolipoprotein B/apolipoprotein A-1 ratio was significantly lower in rats fed diets containing chicory extract or inulin than that in rats fed fiber-free diets, due to significant reductions in apolipoprotein B concentration (P < 0.05). Greater liver lipid and triglyceride concentrations were observed in rats fed chicory extract or inulin diets compared with the controls (P < 0.05). However, liver phospholipid and cholesterol concentrations were not significantly different among groups (P > 0.05). Addition of 5% inulin to the diet resulted in greater cecal weight, whereas both 5% chicory extract and 5% inulin resulted in greater cecal propionic acid concentration compared with the controls (P < 0.05). Rats fed chicory extract and inulin had significantly greater fecal lipid, cholesterol and bile acid excretions than those fed fiber-free diets (P < 0.05). The results of this study suggest that the improved lipid metabolism observed in rats fed chicory extract (mainly inulin component) may be caused by an alteration in the absorption and/or synthesis of cholesterol, which might result from the changes in cecal fermentation, and by an increase in the fecal excretion of lipid, cholesterol and bile acid.

Post-transplant hyperlipidaemia: low-dose lovastatin lowers atherogenic lipids without plasma accumulation of lovastatin.

The purpose of the present study was twofold. First, to determine the frequency of hyperlipidaemia after heart transplantation (Tx) in relation to values obtained before Tx. Secondly, to examine the effect of low-dose lovastatin on possible antiatherogenic mechanisms and test the hypothesis that the side-effects are dose-dependent. Retrospective study of the frequency of hyperlipidaemia disturbances in heart transplant patients. In addition, in a prospective study, the safety and efficacy of incremental low doses of lovastatin up to 20 mg day-1 were studied, with measurements of its plasma concentration in 24 cyclosporin A treated heart (n = 14) and kidney (n = 10) recipients with total cholesterol > 7.5 mmol L-1. Cholesterol increased markedly after heart transplantation from a pretransplant value of 5.3 (5.0,5.6) mmol L-1 to 6.7 (6.4,7.0) mmol L-1 after 1 year and then remained constant, but this increase was largely due to a 'normalization' since cholesterol decreased significantly during increasing heart failure before transplantation. Treatment with lovastatin decreased total cholesterol by 19% (P < 0.001), primarily by an effect on LDL cholesterol. HDL cholesterol increased by 15% (P < 0.05), whereas triglycerides remained unchanged. Lovastatin also caused a significant reduction in apolipoprotein B of 16%, and lipid peroxidation of 40%, whereas apolipoprotein A-I, fibrinogen, and glycerol were unchanged. Plasma concentration of lovastatin was significantly higher in transplant recipients compared with controls, but there was no accumulation during incremental dosing of lovastatin. The drug was well tolerated without significant symptoms or evidence of myopathy. Hyperlipidaemia is common after cardiac transplantation. Treatment with low dose lovastatin is well tolerated and has a favourable effect on atherogenic lipids.

Effectiveness of Low-Dose Crystalline Nicotinic Acid in Men With Low High-Density Lipoprotein Cholesterol Levels

Hypoalphalipoproteinemia (low serum concentration of high-density lipoprotein cholesterol [HDL-C]) is a common pattern of dyslipidemia associated with coronary heart disease. High doses of nicotinic acid effectively raise HDL-C levels in this condition, but they are commonly accompanied by side effects. The efficacy of low doses of nicotinic acid that may produce fewer side effects has not been adequately studied. To determine the effects of low-dose nicotinic acid on HDL-C levels in patients with hypoalphalipoproteinemia. Forty-four men with low HDL-C levels (< 1.03 mmol/L [< 40 mg/dL]) entered the study. Twenty-four patients otherwise had normal lipid levels, and 20 were moderately hypertriglyceridemic (range of plasma triglyceride levels, 2.82 to 5.64 mmol/L 250 to 500 mg/dL). The trial consisted of 3 phases; each phase lasted 8 weeks. The first phase was diet only (30% fat diet); in the second phase, crystalline nicotinic acid was added at 1.5 g/d; and in the third phase, the dose was increased to 3 g/d. Of the 44 patients who entered the study, 37 completed the low-dose phase (1.5 g/d); the remaining patients were withdrawn because of side effects to nicotinic acid. Four other patients who completed the low-dose phase were excluded from the higher dose phase because of side effects that developed when they were receiving the low dose. Ten other patients withdrew during the high-dose phase because of side effects. In both groups, responses to nicotinic acid therapy tended to be dose-dependent. For both groups, the higher dose generally produced a greater reduction in apolipoprotein B-containing lipoproteins and a greater rise in HDL-C levels. However, for both groups, the low dose of nicotinic acid gave an average 20% increase in HDL-C levels. A low dose (1.5 g/d) of crystalline nicotinic acid causes an average 20% increase in HDL-C levels and significantly lowers triglyceride levels in both normolipidemic and hyperlipidemic patients with low HDL-C levels. Although the changes induced by this dose are less than those that can be achieved by a higher dose, the lower dose is better tolerated. Nicotinic acid may be useful in combined drug therapy for secondary prevention of coronary heart disease, and if higher doses cannot be tolerated, use of a lower dose should still be useful for producing a moderate rise in HDL-C levels in patients with hypoalphalipoproteinemia.

Effects of alcohol consumption on pharmacokinetics, efficacy, and safety of fluvastatin

<h2>Abstract</h2> Alcohol consumption is known to have beneficial effects on cardiac mortality, probably by increasing high density lipoprotein cholesterol (HDL-C). Alcohol also increases triglycerides and, in some studies, total cholesterol and low density lipoprotein cholesterol (LDL-C). Nothing is known, however, of the effects of alcohol on the pharmacokinetics and efficacy of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Consequently, 2 studies have been carried out to determine the effects of alcohol consumption on the pharmacokinetics and efficacy of the HMG-CoA reductase inhibitor fluvastatin. Firstly, the effects of acute alcohol consumption on a single, oral 40 mg dose of fluvastatin were examined in a reference-controlled, randomized, crossover study in 10 healthy volunteers. Measurements were made after ingestion of 70 g of ethanol diluted to 20% with lemonade and, following a 7-day period, after ingestion of lemonade alone (reference). The half-life (<i>t</i>_1/2) of a single dose of fluvastatin was significantly reduced by acute alcohol consumption compared with reference, whereas the area under the time—concentration curve (AUC), peak concentration (<i>C</i>_max), and time to peak concentration (<i>t</i>_max) did not differ from the reference group. The lipid profile, measured 8 hr after administration, did not differ significantly from baseline in the reference group, apart from a slight reduction in apolipoprotein (apo)-AI. Triglyceride levels increased with alcohol, probably due to impaired fatty acid oxidation. Surprisingly, total cholesterol and LDL-C fell significantly, possibly due to altered pharmacokinetics, as reflected by the lower <i>t</i>_1/2. To assess the long-term clinical implications of these findings, a 6-week study into the effects of alcohol consumption on fluvastatin pharmacokinetics and lipid-lowering capacity was concluded in 26 patients with primary hypercholesterolemia (LDL-C 4.2 mmol/liter after dietary baseline period). Patients were randomized to 6-week treatment with 40 mg/day of fluvastatin, combined with either 20 g of alcohol diluted to 20% with lemonade, or with lemonade alone (reference). After a 6-week washout period, the 2 groups crossed over for a second 6-week treatment period. Measurements were made at the end of each treatment period. In the 20 patients who completed the study, no serious adverse events occurred. Alcohol did have some effect on fluvastatin pharmacokinetic parameters; a tendency to lengthen <i>t</i>_1/2 and to increase AUC and <i>t</i>_max compared with reference, without a difference in <i>C</i>_max between reference and alcohol. However, these pharmacokinetic effects did not correlate with differences in lipid parameters. Neither reference nor alcohol showed significant changes in HDL-C or triglyceride levels, but significant decreases in total cholesterol, LDL-C, and apo B were observed; these decreases did not differ significantly between reference and alcohol. In conclusion, alcohol consumption has no effect on the efficacy and safety of fluvastatin treatment in patients with primary hypercholesterolemia.

Effects of alcohol consumption on pharmacokinetics, efficacy, and safety of fluvastatin

Alcohol consumption is known to have beneficial effects on cardiac mortality, probably by increasing high density lipoprotein cholesterol (HDL-C). Alcohol also increases triglycerides and, in some studies, total cholesterol and low density lipoprotein cholesterol (LDL-C). Nothing is known, however, of the effects of alcohol on the pharmacokinetics and efficacy of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Consequently, 2 studies have been carried out to determine the effects of alcohol consumption on the pharmacokinetics and efficacy of the HMG-CoA reductase inhibitor fluvastatin. Firstly, the effects of acute alcohol consumption on a single, oral 40 mg dose of fluvastatin were examined in a reference-controlled, randomized, crossover study in 10 healthy volunteers. Measurements were made after ingestion of 70 g of ethanol diluted to 20% with lemonade and, following a 7-day period, after ingestion of lemonade alone (reference). The half-life ( t 1/2) of a single dose of fluvastatin was significantly reduced by acute alcohol consumption compared with reference, whereas the area under the time—concentration curve (AUC), peak concentration ( C max), and time to peak concentration ( t max) did not differ from the reference group. The lipid profile, measured 8 hr after administration, did not differ significantly from baseline in the reference group, apart from a slight reduction in apolipoprotein (apo)-AI. Triglyceride levels increased with alcohol, probably due to impaired fatty acid oxidation. Surprisingly, total cholesterol and LDL-C fell significantly, possibly due to altered pharmacokinetics, as reflected by the lower t 1/2. To assess the long-term clinical implications of these findings, a 6-week study into the effects of alcohol consumption on fluvastatin pharmacokinetics and lipid-lowering capacity was concluded in 26 patients with primary hypercholesterolemia (LDL-C 4.2 mmol/liter after dietary baseline period). Patients were randomized to 6-week treatment with 40 mg/day of fluvastatin, combined with either 20 g of alcohol diluted to 20% with lemonade, or with lemonade alone (reference). After a 6-week washout period, the 2 groups crossed over for a second 6-week treatment period. Measurements were made at the end of each treatment period. In the 20 patients who completed the study, no serious adverse events occurred. Alcohol did have some effect on fluvastatin pharmacokinetic parameters; a tendency to lengthen t 1/2 and to increase AUC and t max compared with reference, without a difference in C max between reference and alcohol. However, these pharmacokinetic effects did not correlate with differences in lipid parameters. Neither reference nor alcohol showed significant changes in HDL-C or triglyceride levels, but significant decreases in total cholesterol, LDL-C, and apo B were observed; these decreases did not differ significantly between reference and alcohol. In conclusion, alcohol consumption has no effect on the efficacy and safety of fluvastatin treatment in patients with primary hypercholesterolemia.

An inhibitor of squalene epoxidase, NB-598, suppresses the secretion of cholesterol and triacylglycerol and simultaneously reduces apolipoprotein B in HepG2 cells

NB-598, a specific inhibitor of squalene epoxidase, suppressed the secretion of cholesterol and triacylglycerol from HepG2 cells into the medium. L-654,969, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, inhibited the secretion of cholesterol as potently as NB-598, but did not suppress the secretion of triacylglycerol. Both compounds decreased the intracellular cholesterol content almost equally, and neither of the compounds reduced the intracellular triacylglycerol content. The suppression of lipid secretion by NB-598 was associated with a significant reduction in apolipoprotein (apo) B secretion into the medium. Therefore, the suppression of lipid secretion by NB-598 may be caused by a reduction in the number of triacylglycerol-rich lipoprotein particles. In contrast, the suppression of cholesterol secretion by L-654,969 may be due to a modulation of lipoprotein lipid composition, since this agent did not reduce the secretion of apo B or triacylglycerol. The secretion of apo A-I was unaffected by either NB-598 or L-654,969. Pulse chase studies using [ 35S]methionine showed that the suppression of apo B secretion by NB-598 depended on an enhancement of intracellular degradation of apo B. These results indicate that the secretion of apo B from HepG2 cells is not regulated by the lipid synthesis alone, and suggest that the mechanism of the hypolipidemic effect of NB-598 involves the suppression of triacylglycerol-rich lipoprotein secretion from the liver as well as an inhibition of cholesterol synthesis in the liver.

Long Term Treatment with Pravastatin, Simvastatin and Gemfibrozil in Patients with Primary Hypercholesterolaemia: A Controlled Study

Patients with primary hypercholesterolaemia (30 with familial hypercholesterolaemia and 17 with polygenic hypercholesterolaemia), were randomly treated with either simvastatin or pravastatin 40 mg/day or gemfibrozil 1200 mg/day for up to 18 months. Efficacy and safety parameters were measured every 3 months. To date, out of the initial 47 subjects who entered the study, 38 have been treated for 12 months and 34 for 18 months. Both simvastatin and pravastatin lowered total and low density lipoprotein (LDL) cholesterol (by about 30%). This effect was already maximal by the third month of therapy and the decrease was maintained for up to 18 months. The effect of gemfibrozil on these lipid parameters was slower (maximum lowering effect at the sixth month) and less marked during the first 6 months of therapy. However, after the sixth month the differences between the 3 drugs were no longer statistically significant, possibly because of large interindividual variability in the response to treatment. All 3 treatment groups had similar reductions in apolipoprotein- (Apo) A1 and Apo-B levels. High density lipoprotein (HDL) cholesterol levels were increased significantly during treatment with gemfibrozil, but not during therapy with either of the statins. However, intergroup analysis did not reveal consistent differences in HDL-cholesterol during treatment. Gemfibrozil markedly decreased triglyceride levels, and this effect was maintained throughout the study. Neither simvastatin nor pravastatin affected triglyceride levels. The statins therefore did not show different influences on any lipid parameter studied. All 3 drugs were well tolerated. Simvastatin was, however, associated with significant increases in GGT and CPK activities at the 6-month evaluation. In conclusion, there were no significant differences between simvastatin, pravastatin or gemfibrozil in long term effects on total, LDL- and HDL-cholesterol levels in patients with primary hypercholesterolaemia, although this finding may have been due to large interindividual variations in the response to therapy. It would therefore appear that gemfibrozil is an effective lipid-lowering agent which is suitable for long term treatment.

Serum lipid and lipoprotein abnormalities in human African trypanosomiasis

We have studied the serum lipoprotein system in human African trypanosomiasis ( Trypanosoma brucei gambiense infection). The study was carried out on 74 Congolense patients suffering from sleeping sickness and 34 Congolense control subjects living in the endemic region of Boko Songho. We have determined the serum concentrations of lipids (triglycerides, cholesterol, phospholipids) and apolipoproteins (apolipoprotein A-I and B), and the separation of serum lipoproteins by electrophoresis. For the patients infected with T. b. gambiense, in comparison with control subjects, the results have shown (i) a significant increase in triglyceride concentration and a decrease in cholesterol concentration; (ii) a significant rise in apolipoprotein B concentration and a significant reduction in apolipoprotein A-I concentration; and (iii) an increase in low density lipoproteins and a decrease in high density lipoproteins. We conclude, therefore, that human African trypanosomiasis is associated with marked alterations in the composition and levels of host lipoproteins.