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1.
J Clin Invest ; 91(2): 677-83, 1993 Feb.
Article in English | MEDLINE | ID: mdl-8432868

ABSTRACT

The presence of lecithin:cholesterol acyltransferase (LCAT) deficiency in six probands from five families originating from four different countries was confirmed by the absence or near absence of LCAT activity. Also, other invariate symptoms of LCAT deficiency, a significant increase of unesterified cholesterol in plasma lipoproteins and the reduction of plasma HDL-cholesterol to levels below one-tenth of normal, were present in all probands. In the probands from two families, no mass was detectable, while in others reduced amounts of LCAT mass indicated the presence of a functionally inactive protein. Sequence analysis identified homozygous missense or nonsense mutations in four probands. Two probands from one family both were found to be compound heterozygotes for a missense mutation and for a single base insertion causing a reading frame-shift. Subsequent family analyses were carried out using mutagenic primers for carrier identification. LCAT activity and LCAT mass in 23 genotypic heterozygotes were approximately half normal and clearly distinct from those of 20 unaffected family members. In the homozygous patients no obvious relationship between residual LCAT activity and the clinical phenotype was seen. The observation that the molecular defects in LCAT deficiency are dispersed in different regions of the enzyme suggests the existence of several functionally important structural domains in this enzyme.


Subject(s)
Alleles , Lecithin Cholesterol Acyltransferase Deficiency/genetics , Phosphatidylcholine-Sterol O-Acyltransferase/genetics , Adolescent , Adult , Base Sequence , Female , Humans , Male , Middle Aged , Molecular Sequence Data , Mutation , Phenotype , Phosphatidylcholine-Sterol O-Acyltransferase/metabolism
2.
Biochim Biophys Acta ; 1046(1): 64-72, 1990 Aug 28.
Article in English | MEDLINE | ID: mdl-2397246

ABSTRACT

The chemical composition and the physical properties of lipoproteins (VLDL, LDL and HDL) were studied in two groups of patients: 14 healthy normolipidemic subjects and 15 type IIa familial hypercholesterolemic patients. The steady-state fluorescence anisotropy rs was estimated in lipoproteins by the fluorescence depolarization of two fluorescent probes: the DPH (1,6-diphenyl-1,3,5-hexatriene) and the TMA-DPH (1,4-trimethylammonium phenyl-6-1,3,5-hexatriene). A structured order parameter S was calculated from the DPH fluorescence anisotropy. The flow activation energies were calculated for LDL and HDL from both groups from the Arrhenius plots (log r DPH versus 1/T). By using TNBS (trinitrobenzene sulfonic acid) as a distance control quencher, the two probes were located in the outer shell of LDL. In HDL, TMA-DPH remained at the surface of the particles, while DPH was more deeply embedded in the lipid core. There was no difference in the physico-chemical properties of VLDL between the two groups studied. DPH fluorescence anisotropies were significantly increased in LDL and HDL from the hypercholesterolemic group compared to the control particles (P less than 0.05 and P less than 0.01, respectively). In LDL this modification of the fluorescence anisotropy can be related to a change in the lipid composition of particles. LDL from hypercholesterolemic patients contained significantly less triacylglycerol (P less than 0.01) and more cholesteryl ester (N.S.). Their cholesteryl ester to triacylglycerol ratio was significantly higher. In HDL, there was no difference in chemical composition between the two groups. The increase in DPH fluorescence anisotropy can be related to the presence of smaller particles in HDL from HC group. No difference was noted in the TMA-DPH fluorescence anisotropy at 37 degrees C in the LDL from the two groups. In contrast, TMA-DPH fluorescence anisotropy in HDL from hypercholesterolemic group was significantly higher than in control HDL. The flow activation energy of DPH was also significantly higher in both LDL and HDL from the hypercholesterolemic group than in control group particles. In both LDL and HDL from the control group, DPH fluorescence anisotropy was negatively correlated with TG/protein and TG/PL ratios and positively correlated with the CE/TG ratio. No correlation was observed between lipid composition and DPH fluorescence anisotropy values in hypercholesterolemic particles. The modification in fluidity parameters, especially the increase in the flow activation energies in LDL and HDL from hypercholesterolemic patients, could lead to a restriction of cholesterol movements in these particles. From a physiological point of view, this could represent a loss of functional capacity.


Subject(s)
Hyperlipoproteinemia Type II/metabolism , Lipoproteins, HDL , Lipoproteins, LDL , Lipoproteins, VLDL , Adult , Chemical Phenomena , Chemistry, Physical , Cholesterol/blood , Electrophoresis, Polyacrylamide Gel , Fluorescence Polarization , Humans , Hyperlipoproteinemia Type II/blood , Lipoproteins, HDL/blood , Lipoproteins, LDL/blood , Lipoproteins, VLDL/blood , Triglycerides/blood
3.
Biochim Biophys Acta ; 875(2): 174-82, 1986 Feb 12.
Article in English | MEDLINE | ID: mdl-3942761

ABSTRACT

The purpose of this work was to determine whether the changes induced by dietary manipulations in the chemical composition of high-density lipoproteins (HDL) (particularly phospholipid fatty acid composition) modified their capacity to promote [3H]cholesterol efflux from cultured fibroblasts. Plasma HDL were obtained from subjects fed for six successive long periods on diets consisting of one predominant fat: peanut oil, corn oil, olive oil, soybean oil, low erucic acid rapeseed oil or milk fats. The [3H]cholesterol efflux from cells in the presence of plasma HDL was studied by means of normal adult human fibroblasts in culture. The [3H]cholesterol efflux from fibroblasts appeared to be independent of the overall composition of HDL and of the degree of saturation of the HDL phospholipid fatty acids, but it was correlated with the phospholipid fatty acid chain length. The [3H]cholesterol efflux from fibroblasts is highly and positively correlated with the sum of the HDL phospholipid C20, C22, C24 fatty acids, and negatively correlated with the sum of the HDL phospholipid C18 fatty acids.


Subject(s)
Cholesterol/metabolism , Dietary Fats/administration & dosage , Fatty Acids/analysis , Lipoproteins, HDL/analysis , Phospholipids/analysis , Adult , Aged , Biological Transport , Cells, Cultured , Dietary Fats/pharmacology , Female , Fibroblasts/metabolism , Humans , Middle Aged , Structure-Activity Relationship
4.
Biochim Biophys Acta ; 1043(1): 43-51, 1990 Mar 12.
Article in English | MEDLINE | ID: mdl-2310759

ABSTRACT

The present study was undertaken to analyze whether the changes induced by dietary manipulations in the chemical composition of HDL, particularly in total phospholipids, phosphatidylcholine and sphingomyelin fatty acid composition, modified their fluidity. 12 healthy women, aged 26-49 years were studied. They consumed, over periods of 5 weeks, various isocaloric diets, each containing 30% of the calories as fat. 15.6% of the total calories were provided successively by olive oil, soybean oil, corn oil, and milk fats. The HDL fluorescence anisotropy was measured with 1,6-diphenyl-1,3,5-hexatriene (DPH) by fluorescence polarization. The HDL from the monounsaturated diet, olive oil, were the most fluid particles. The HDL fluorescence anisotropy was positively correlated with their free cholesterol percentage and negatively correlated with their triacylglycerol content and their triacylglycerol/phospholipid ratio. Moreover, the HDL fluorescence anisotropy was negatively correlated with the percentage of oleic acid in their total phospholipids and particularly in the phosphatidylcholine. These results suggest that the percentages of triacylglycerol and oleic acid in phospholipids of HDL have a fluidifying effect on these lipoproteins.


Subject(s)
Dietary Fats/pharmacology , Fatty Acids/blood , Lipoproteins, HDL/blood , Adult , Animals , Chemical Phenomena , Chemistry, Physical , Corn Oil/pharmacology , Diphenylhexatriene , Female , Fluorescence Polarization , Humans , Middle Aged , Milk , Oleic Acid , Oleic Acids/blood , Olive Oil , Phosphatidylcholines/blood , Plant Oils/pharmacology , Soybean Oil/pharmacology , Sphingomyelins/blood , Triglycerides/blood
5.
Diabetes ; 33(5): 438-43, 1984 May.
Article in English | MEDLINE | ID: mdl-6373452

ABSTRACT

It has been reported that sand rats, naturally feeding on low-caloric-value plants containing a high concentration of salt, become obese and develop hyperglycemia when fed on a standard laboratory diet. The aim of this study was to examine the long-term effects of a synthetic-chow diet on the metabolic pattern of the diabetic syndrome in a large group of sand rats. While a few animals had a fulminant reaction with markedly decreased glucose tolerance, low plasma insulin levels, and death within 3-4 wk, most sand rats developed obesity and elevated plasma insulin levels. From the third month and forward, 40% of sand rats presented with a diabetic syndrome with hyperinsulinemia, hyperglycemia, markedly decreased glucose tolerance, and insulin resistance. This diabetic syndrome can be compared with maturity-onset (type II) diabetes. When this synthetic-chow diet was given for more than 6 mo, the majority of animals lost considerable weight and showed a major depletion of fat stores. Serum immunoreactive insulin levels fell, while blood glucose rose to above 500 mg/dl with glycosuria and ketonuria. The elevated triglyceride content of plasma and the lipid deposits in the liver were greatly augmented, and no glycogen was present. Animals developed frank insulin-dependent diabetes, and diabetic animals not treated with insulin died in diabetic coma with presumed ketoacidosis. The disease was essentially confined to sand rats showing abnormal glucose tolerance, even before eating laboratory chow. This observation suggests a genetic factor. Thus, the sand rat appears to be a potentially interesting model for investigation of both maturity-onset and insulin-dependent diabetes.


Subject(s)
Animal Feed/adverse effects , Arvicolinae/physiology , Diabetes Mellitus/veterinary , Animals , Blood Glucose/metabolism , Body Weight , Diabetes Mellitus/etiology , Diabetes Mellitus/physiopathology , Disease Models, Animal , Energy Intake , Female , Glucose Tolerance Test , Glycogen/metabolism , Glycosuria/urine , Insulin/blood , Ketone Bodies/metabolism , Liver/metabolism , Male
6.
Eur J Hum Genet ; 8(8): 621-30, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10952765

ABSTRACT

Autosomal dominant type IIa hypercholesterolaemia (ADH) is characterised by an elevation of total plasma cholesterol associated with increased LDL particles. Numerous different molecular defects have been identified in the LDL receptor (LDLR) and few specific mutations in the apolipoprotein B (APOB) gene resulting in familial hypercholesterolaemia and familial defective apoB-100 respectively. To estimate the respective contribution of LDLR, APOB and other gene defects in this disease, we studied 33 well characterised French families diagnosed over at least three generations with ADH through the candidate gene approach. An estimation of the proportions performed with the HOMOG3R program showed that an LDLR gene defect was involved in approximately 50% of the families (P = 0.001). On the other hand, the estimated contribution of an APOB gene defect was only 15%. This low estimation of ADH due to an APOB gene defect is further strengthened by the existence of only two probands carrying the APOB (R3500Q) mutation in the sample. More importantly and surprisingly, 35% of the families in the sample were estimated to be linked to neither LDLR nor APOB genes. These data were confirmed by the exclusion of both genes through direct haplotyping in three families. Our results demonstrate that the relative contributions of LDLR and APOB gene defects to the disease are very different. Furthermore, our results also show that genetic heterogeneity is, generally, underestimated in ADH, and that at least three major groups of defects are involved. At this point, the contribution of the recently mapped FH3 gene to ADH cannot be assessed nor its importance in the group of 'non LDLR/non APOB' families.


Subject(s)
Apolipoproteins B/genetics , Hyperlipoproteinemia Type II/genetics , Receptors, LDL/genetics , Cholesterol, LDL/analysis , Chromosome Mapping , Chromosomes, Human, Pair 1 , Female , Genetic Heterogeneity , Genetic Linkage , Haplotypes , Humans , Lod Score , Male , Mathematical Computing , Microsatellite Repeats , Pedigree , Sequence Analysis, DNA , Triglycerides/analysis
7.
Free Radic Biol Med ; 22(6): 1037-45, 1997.
Article in English | MEDLINE | ID: mdl-9034243

ABSTRACT

Oxidative modifications of lipoproteins could contribute to the development of atherosclerosis, but the influence of dietary fats on high density lipoprotein (HDL) oxidative modification is unknown. This study was designed to determine whether a diet rich in oleic acid could modulate the oxidative modification of HDL3. Twenty two healthy men were randomly placed on a 32-wk crossover study of an oleic acid rich diet supplied by a variant of sunflower oil vs a linoleic acid rich diet provided by conventional sunflower oil. Plasma HDL3 obtained after the diet rich in oleic acid showed a significantly higher oleic acid content in the phospholipid than lipoprotein isolated after the linoleic acid rich diet. HDL3 isolated after the oleic acid rich diet had lower values of thiobarbituric acid reactive substances (TBARS) than HDL3 obtained after the linoleic acid rich diet both for native (mean +/- SE; 0.24 +/- 0.02 vs 0.42 +/- 0.08 nmol MDA/mg protein; p < 0.01) and copper oxidized HDL3 (0.75 +/- 0.06 vs 0.95 +/- 0.07 nmol MDA/mg protein; p < 0.01). Indeed, TBARS for native HDL3 were negatively correlated with the oleic acid to linoleic acid ratio and positively with the percentage of linoleic acid in their phospholipids. Interestingly, HDL3 after both diets had similar antioxidant vitamins A and E content. HDL3 overall composition and fluidity were similar after the two diets. Moreover, HDL3 obtained after both diets produced identical [3H] free cholesterol efflux from human monocyte-derived macrophages (29%) and fibroblasts (26%). In conclusion, HDL3 rich in oleic acid was less easily oxidized regardless of the content of antioxidants such as vitamins A and E. Therefore, dietary monounsaturated fatty acid prevent the oxidative modification of lipoproteins.


Subject(s)
Dietary Fats, Unsaturated/administration & dosage , Lipid Peroxidation , Lipoproteins, HDL/blood , Cholesterol/blood , Copper , Cross-Over Studies , Fluorescence Polarization , Humans , Linoleic Acid , Linoleic Acids/administration & dosage , Macrophages/metabolism , Male , Middle Aged , Oleic Acids/administration & dosage , Oxidation-Reduction , Plant Oils , Sunflower Oil , Thiobarbituric Acid Reactive Substances/metabolism , Vitamin A/blood , Vitamin E/blood
8.
Atherosclerosis ; 58(1-3): 261-8, 1985 Dec.
Article in English | MEDLINE | ID: mdl-4091882

ABSTRACT

In this study Probucol transport and the effect of the drug on lipoprotein composition in 9 cases of type IIa hypercholesterolemia were investigated. Probucol lowered plasma cholesterol by 20%, without affecting triglycerides. HDL cholesterol was decreased and a slight reduction in LDL cholesterol was noted. This was due to a reduction in the number of circulating lipoprotein particles, without modification in the lipid/protein ratio, mainly cholesterol/protein ratio. Probucol was almost entirely removed by lipoproteins; 75% of the drug was found in LDL, the remainder being equally distributed in VLDL and HDL. There was no correlation between the serum Probucol level, or the amount of Probucol bound to lipoproteins, and the decrease in serum or lipoprotein cholesterol. However, there was a significant increase of the EC/TC (esterified cholesterol/total cholesterol) ratio in VLDL and LDL, but not in HDL.


Subject(s)
Hyperlipoproteinemia Type II/drug therapy , Lipoproteins/blood , Phenols/pharmacology , Probucol/pharmacology , Adult , Aged , Biological Transport, Active , Cholesterol/blood , Cholesterol Esters/blood , Female , Humans , Hyperlipoproteinemia Type II/blood , Lipoproteins, LDL/blood , Lipoproteins, VLDL/blood , Male , Middle Aged , Probucol/blood
9.
Atherosclerosis ; 24(3): 441-50, 1976 Sep.
Article in English | MEDLINE | ID: mdl-971346

ABSTRACT

The incidence of ischaemic diseases in familial hypercholesterolaemia and xanthomatosis (familial Type II) was studied in a group of 158 men and 116 women. (1) Men and women did not differ with regard to the inherited metabolic disease. Levels of serum cholesterol, the marker of the genetic defect, were not statistically different, and cholesterol deposition in tissues, visualized by skin tendon xanthomas, was not sex related. (2) Men and women were different with regard to ischaemic diseases. The incidence was much lower in women, and the mean age of onset 9 years later. Moreover, there was a sex difference in the nature of the ischaemic disease, with a high male predominance of myocardial infarction. (3) Since the major risk factor hypercholesterolaemia could not explain such a difference, the role of other risk factors was investigated. It was shown that the incidence of ischaemic diseases was increased in women by cigarette smoking and hypertension, and that the difference in age of onset between males and females was no longer seen in smoking women. It is suggested that the genetic factor is responsible for the atherosclerotic lesion in both sexes and that other factors playing a role in ischaemic complications including tobacco and hypertension may explain the difference between men and women.


Subject(s)
Coronary Disease/complications , Heterozygote , Hypercholesterolemia/complications , Xanthomatosis/complications , Adult , Cholesterol/blood , Coronary Disease/genetics , Female , Humans , Hypercholesterolemia/genetics , Hypertension/complications , Male , Middle Aged , Muscular Diseases/complications , Myocardial Infarction/complications , Obesity/complications , Risk , Sex Factors , Smoking , Tendons , Triglycerides/blood , Uric Acid/blood , Xanthomatosis/genetics
10.
Atherosclerosis ; 140(2): 281-95, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9862271

ABSTRACT

This review proposes reinvestigation of a topic studied in the author's laboratory over the last decades concerning the age-dependent modifications of the vascular extracellular matrix (ECM) as related to atherogenesis and its recognized risk-factors: blood lipids, lipoproteins. Most salient previous results are confronted with recent publications in this field. Age-dependent modifications of the vascular wall discussed in this review include upregulation of elastolytic enzymes, demonstrated for the first time in the vascular wall in this laboratory, matrix biosynthesis and receptor function. The progressive deposition of lipids in elastic tissues as well as the addition of lipoproteins or lipids to cell and organ cultures were shown to modify matrix biosynthesis and upregulate elastase expression. Lipid-elastin interactions exhibit a great deal of specificity as shown by the nature and amount of lipids accumulating in elastin in vivo and in vitro. Recent epidemiological studies (the EVA study) enables the confrontation of blood lipid parameters with matrix related components (serum elastase and inhibitors, elastin peptides, fibronectin) in the same blood samples. The elastin laminin receptor present on vascular cells was shown to trigger NO dependent vasodilation, and downregulation of cholesterol synthesis. Both of these functions decrease or disappear with age except the upregulation of elastase release which is preserved and increased. Recent experiments extended these findings to T-lymphocytes present also in the atherosclerotic plaque. Finally several recent publications are analyzed which give more precision on the cellular mechanisms underlying the above-described modifications.


Subject(s)
Arteries/metabolism , Arteriosclerosis/metabolism , Elastin/metabolism , Pancreatic Elastase/metabolism , Adult , Aged , Aging/metabolism , Aging/pathology , Animals , Arteries/pathology , Arteries/physiopathology , Arteriosclerosis/etiology , Arteriosclerosis/pathology , Cholesterol/biosynthesis , Extracellular Matrix/metabolism , Female , Humans , Male , Middle Aged , Rabbits , Risk Factors , Vasodilation
11.
Atherosclerosis ; 62(1): 65-71, 1986 Oct.
Article in English | MEDLINE | ID: mdl-3778575

ABSTRACT

A possible mechanism of action of probucol on low density lipoprotein uptake was examined in 7 type IIa hypercholesterolemic subjects. Probucol administration effectively lowered plasma cholesterol. Both apo B-associated cholesterol and HDL cholesterol were decreased but a great inter-patient variability was noted. Plasma triglycerides were unchanged and phospholipids decreased. The composition of the isolated LDL was unaffected. The LDL displaceable activity of reference [125I]LDL measured by competition assays in control fibroblasts, was increased in 3 subjects, decreased in 1 subject and unchanged in the other 3. No correlation was found between the change in apo B-associated cholesterol and the change in the in vitro catabolism of LDL of treated patients. The results did not allow a simple mechanism of action to be ascribed to the drug, but questioned the origin of the hypercholesterolemia.


Subject(s)
Hyperlipoproteinemia Type II/blood , Lipoproteins, LDL/blood , Phenols/therapeutic use , Probucol/therapeutic use , Skin/metabolism , Adult , Aged , Cells, Cultured , Female , Fibroblasts/metabolism , Humans , Hyperlipoproteinemia Type II/drug therapy , Lipoproteins, LDL/metabolism , Male , Middle Aged
12.
Atherosclerosis ; 113(1): 1-9, 1995 Feb.
Article in English | MEDLINE | ID: mdl-7755644

ABSTRACT

The effect of gemfibrozil treatment on very low (VLDL) and low (LDL) density lipoprotein subfractions has been investigated in 9 moderate hypertriglyceridemic (HTG) patients (triglyceride (TG) levels 237-426 mg/dl). Three VLDL subfractions, VLDL1 (Sf 175-400), VLDL2 (Sf 100-175) and VLDL3 (Sf 20-100) and 4 LDL subspecies, LDL1 (1.023-1.028 g/ml), LDL2 (1.029-1.037 g/ml), LDL3 (1.038-1.049 g/ml) and LDL4 (1.050-1.062 g/ml) were prepared by density gradient ultracentrifugation. High density lipoprotein (HDL) chemical composition and lipolytic activities after heparin injection were also determined. Gemfibrozil induced a net decrease in VLDL1 and VLDL2 concentrations (P < 0.01). Cholesteryl ester (CE) weight percent was significantly reduced in both VLDL1 and VLDL2 subfractions. VLDL3 concentration and composition were not changed by the treatment. Lipoprotein lipase (LPL) activity was reduced in HTG patients (P < 0.05). After treatment, LPL activity increased (P < 0.05) but remained lower than in control, normotriglyceridemic (NTG) subjects. Furthermore, gemfibrozil increased HDL cholesterol (P < 0.05) and normalised the elevated HDL2 and HDL3 TG content. The increase of LDL cholesterol, often observed after gemfibrozil treatment, was due to a rise in the LDL2 subfraction (1.029 < d < 1.037 g/ml), the main fraction present in control subjects. However, despite the significant decrease of total plasma TG (329 mg/dl vs. 174 mg/dl), LDL3 subfraction (1.038 < d < 1.049 g/ml) was not reduced.


Subject(s)
Gemfibrozil/therapeutic use , Hypertriglyceridemia/drug therapy , Lipoproteins, LDL/blood , Lipoproteins, VLDL/blood , Adult , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Humans , Hypertriglyceridemia/blood , Hypertriglyceridemia/enzymology , Lipoprotein Lipase/metabolism , Lipoproteins, HDL/blood , Male , Middle Aged , Triglycerides/blood
13.
Atherosclerosis ; 91 Suppl: S29-34, 1991 Dec.
Article in English | MEDLINE | ID: mdl-1789814

ABSTRACT

This study compares the effects of fenofibrate and simvastatin in primary hypercholesterolemia, with particular regard to lipoprotein particles, as defined by their apolipoprotein composition: LpAI, LpAII: AI, LpE:B, LpCIII:B. This was a double-blind study in which patients were randomized to 2 groups, one receiving simvastatin 20 mg once daily and the other receiving fenofibrate 200 mg b.i.d., if their total cholesterol and their LDL cholesterol remained above 7.60 mmol/l (300 mg/dl) and 4.95 mmol/l (195 mg/dl) after a 4-week placebo period. Simvastatin dosage was doubled at the end of 6 weeks of therapy if the LDL-cholesterol level remained above 3.55 mmol/l (140 mg/dl). Analyses were done after 6 and 10 weeks of therapy. Apolipoprotein AI was increased significantly only at week 10 with fenofibrate (+7.4%). Simvastatin had a more pronounced effect than fenofibrate on apolipoprotein B. There was a significant difference between drugs at weeks 6 and 10. No change was observed in the LpAII:AI level with simvastatin, whereas fenofibrate increased these particles quite significantly (+13.9 and +22.3%). The drugs had opposite effects on LpAI (+2.5 and +5.6% with simvastatin; -12.8 and -15.1% with fenofibrate). LP E:B (-33.0 and -40.8% with simvastatin; -53.8 and -52.2% with fenofibrate) and LpCIII:B (-23.8 and -31.8% with simvastatin; -35.1 and -43.5% with fenofibrate) were decreased by both drugs, but fenofibrate was significantly more effective in reducing these particles than simvastatin at week 6. This study suggests that both drugs led to different structural modifications of the lipoproteins, which would not be revealed by total apolipoprotein analysis. These differences are probably related to the mechanisms of action of these drugs.


Subject(s)
Anticholesteremic Agents/therapeutic use , Apolipoproteins/analysis , Fenofibrate/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Hypercholesterolemia/drug therapy , Lipoproteins/analysis , Lovastatin/analogs & derivatives , Adolescent , Adult , Aged , Apolipoprotein A-I/analysis , Apolipoprotein A-II/analysis , Apolipoproteins B/analysis , Double-Blind Method , Humans , Hypercholesterolemia/blood , Lovastatin/therapeutic use , Middle Aged , Simvastatin
14.
Atherosclerosis ; 143(2): 415-25, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10217372

ABSTRACT

The aim of the present study was to search in type IIb hyperlipidemic patients for putative concomitant effects of simvastatin on the physicochemical characteristics of low density lipoproteins (LDL) and high density lipoproteins (HDL), as well as on the activities of the cholesteryl ester transfer protein (CETP) and the phospholipid transfer protein (PLTP) that were determined in both endogenous lipoprotein-dependent and endogenous lipoprotein-independent assays. In a double-blind, randomized trial, patients received either placebo (one tablet/day; n = 12) or simvastatin (20 mg/day; n = 12) for a period of 8 weeks after a 5-week run-in period. Simvastatin, unlike placebo, reduced the lipid and apolipoprotein B contents of the most abundant LDL-1, LDL-2, and LDL-3 subfractions without inducing significant changes in the overall size distribution of LDL and HDL. Whereas simvastatin significantly increased PLTP activity in an endogenous lipoprotein-dependent assay (P < 0.01), no variation was observed in a lipoprotein-independent assay. Simvastatin significantly decreased plasma CETP activity in an endogenous lipoprotein-dependent assay (P < 0.01), and the reduction in plasma cholesteryl ester transfer rates was explained by a 16% drop in CETP mass concentration (P < 0.01). In contrast, the specific activity of CETP was unaffected by the simvastatin treatment reflecting at least in part the lack of significant alteration in plasma triglyceride-rich lipoprotein acceptors. The simvastatin-induced changes in plasma CETP mass levels correlated positively with changes in plasma CETP activity (r = 0.483, P = 0.0561), in total cholesterol levels (r = 0.769; P < 0.01), and in LDL-cholesterol levels (r = 0.736; P < 0.01). Whereas the observations suggest that simvastatin might exert concomitant beneficial effects on plasma CETP and LDL levels, neither plasma cholesteryl ester transfer activity nor plasma phospholipid transfer activity appeared as the main determinants of the LDL and HDL distribution profiles in type IIb hyperlipidemic patients.


Subject(s)
Carrier Proteins/drug effects , Glycoproteins , Hyperlipoproteinemia Type II/blood , Hyperlipoproteinemia Type II/drug therapy , Hypolipidemic Agents/administration & dosage , Membrane Proteins/drug effects , Phospholipid Transfer Proteins , Simvastatin/administration & dosage , Adult , Aged , Carrier Proteins/blood , Cholesterol Ester Transfer Proteins , Double-Blind Method , Enzyme-Linked Immunosorbent Assay , Female , Humans , Lipoproteins, HDL/blood , Lipoproteins, HDL/drug effects , Lipoproteins, LDL/blood , Lipoproteins, LDL/drug effects , Male , Membrane Proteins/blood , Middle Aged , Reference Values , Treatment Outcome
15.
Am J Med ; 96(6A): 87S-93S, 1994 Jun 06.
Article in English | MEDLINE | ID: mdl-8017473

ABSTRACT

In this long-term (52-week) open-label extension to an earlier randomized, multicenter, double-blind, placebo-controlled, dose-finding trial, 381 patients with primary hypercholesterolemia received fluvastatin at increasing doses of 10 to 40 mg/day to achieve plasma low-density lipoprotein (LDL) cholesterol normalization, according to the European Atherosclerosis Society guidelines. The aim of the extension study was to assess the long-term efficacy, safety, and tolerability of fluvastatin. After 52 weeks of therapy, 75% of patients were receiving fluvastatin at 40 mg/day (mean dose: 36 +/- 8 mg/day). The mean percent change in LDL-cholesterol levels from baseline was -24.8% (p < 0.001), and 82.6% of patients achieved an LDL-cholesterol reduction of > or = 15%. In patients in the lowest baseline quintile, high-density lipoprotein-cholesterol levels were significantly (p < 0.001) increased by 8.8% whereas, in the highest baseline quintile, triglycerides were significantly (p < 0.001) reduced by 15.3%. Plasma lipoparticle (a) [Lp(a)]:B levels were also significantly reduced (-38.6%; p < 0.001). Fluvastatin was considered to be well tolerated by the majority of patients by both patients and investigators. The most frequently reported adverse event was abdominal pain. Notable biochemical abnormalities were rare. In conclusion, the results of this extension study indicate that fluvastatin at dosages of 20-40 mg/day is effective and well tolerated in patients with primary hypercholesterolemia and is accompanied by no particular problems of safety.


Subject(s)
Anticholesteremic Agents/therapeutic use , Fatty Acids, Monounsaturated/therapeutic use , Hypercholesterolemia/drug therapy , Indoles/therapeutic use , Adult , Aged , Anticholesteremic Agents/adverse effects , Fatty Acids, Monounsaturated/adverse effects , Female , Fluvastatin , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Indoles/adverse effects , Male , Middle Aged , Time Factors
16.
Am J Cardiol ; 76(2): 54A-56A, 1995 Jul 13.
Article in English | MEDLINE | ID: mdl-7604799

ABSTRACT

Following a 6-week placebo period, 134 patients with low density lipoprotein cholesterol (LDL-C) > or = 160 mg/dL and plasma triglyceride < or = 400 mg/dL, despite following a standard lipid-lowering diet, were randomized to double-blind, double-placebo treatment with fluvastatin (22 women, 46 men; age 21-71 years) or pravastatin (25 women, 41 men; age 19-76 years). Fluvastatin at 40 mg and pravastatin at 20 mg were given for the first 4 weeks, both once daily with the evening meal. For the following 12 weeks, fluvastatin at 40 mg twice daily and pravastatin at 40 mg once daily were given with the evening meal. Both drugs were equally effective in lowering LDL-C after 4 weeks of treatment (-24.0% with fluvastatin, -24.1% with pravastatin) but, after 16 weeks, LDL-C reduction was -30.4% with fluvastatin and -26.6% with pravastatin. This further lowering of LDL-C between week 4 and week 16 was significant (p < 0.001) for fluvastatin but not pravastatin. Adverse events were reported by 23 fluvastatin patients and 22 pravastatin patients: 3 patients in each group withdrew from the study because of these. No notable abnormalities in levels of alanine or aspartate aminotransferase values (defined as > 3 times the upper limit of normal on 2 consecutive occasions) or of creatine phosphokinase (defined as > 10 times the upper limit of normal on any occasion) were observed in either treatment group.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Anticholesteremic Agents/therapeutic use , Fatty Acids, Monounsaturated/therapeutic use , Hydroxymethylglutaryl CoA Reductases/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Hypercholesterolemia/drug therapy , Indoles/therapeutic use , Pravastatin/therapeutic use , Adult , Aged , Alanine Transaminase/blood , Anticholesteremic Agents/administration & dosage , Anticholesteremic Agents/adverse effects , Aspartate Aminotransferases/blood , Cholesterol/blood , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Creatine Kinase/blood , Double-Blind Method , Fatty Acids, Monounsaturated/administration & dosage , Fatty Acids, Monounsaturated/adverse effects , Female , Fluvastatin , Humans , Hydroxymethylglutaryl CoA Reductases/administration & dosage , Hydroxymethylglutaryl CoA Reductases/adverse effects , Hypercholesterolemia/blood , Indoles/administration & dosage , Indoles/adverse effects , Male , Middle Aged , Placebos , Pravastatin/administration & dosage , Pravastatin/adverse effects , Triglycerides/blood
17.
Am J Cardiol ; 76(2): 41A-46A, 1995 Jul 13.
Article in English | MEDLINE | ID: mdl-7604796

ABSTRACT

Fluvastatin monotherapy up to 40 mg/day over 52 weeks in patients with primary hypercholesterolemia decreased plasma low density lipoprotein cholesterol (LDL-C) by 28%, with varying decreases in plasma triglycerides and increases in high density lipoprotein cholesterol (HDL-C). Patients completing the 52-week study participated in a further trial to assess whether the efficacy of fluvastatin (20-40 mg/day), either as monotherapy or in combination with cholestyramine (CME; 4-16 g/day), taken at least 4 hours prior to fluvastatin, is sustained for up to 3 years. Patients were assessed every 12 weeks on average for safety and efficacy, the latter being calculated as a percent change from baseline of lipids or lipoproteins. During the second year (endpoint up to week 104), 147 patients received monotherapy (estimated mean dose, 30.2 mg/day) and 127 received additional CME (38.1 mg/day fluvastatin plus 10.1 g/day CME). During the third year (endpoint up to week 156), 140 patients received monotherapy (32.5 mg/day) and 67 received additional CME (39.3 mg/day fluvastatin plus 10.3 mg/day CME). Statistically significant reductions in mean total cholesterol and LDL-C and increases in mean HDL-C were achieved in both treatment groups and maintained throughout the study. A significant reduction in triglyceride levels was only observed at the second year endpoint in patients receiving monotherapy (-10.0%).(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Anticholesteremic Agents/therapeutic use , Cholestyramine Resin/therapeutic use , Fatty Acids, Monounsaturated/therapeutic use , Hydroxymethylglutaryl CoA Reductases/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Hypercholesterolemia/drug therapy , Indoles/therapeutic use , Anticholesteremic Agents/administration & dosage , Anticholesteremic Agents/adverse effects , Cholesterol/blood , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Cholestyramine Resin/administration & dosage , Cholestyramine Resin/adverse effects , Cohort Studies , Drug Combinations , Fatty Acids, Monounsaturated/administration & dosage , Fatty Acids, Monounsaturated/adverse effects , Female , Fluvastatin , Humans , Hydroxymethylglutaryl CoA Reductases/administration & dosage , Hydroxymethylglutaryl CoA Reductases/adverse effects , Hypercholesterolemia/blood , Indoles/administration & dosage , Indoles/adverse effects , Longitudinal Studies , Male , Middle Aged , Retrospective Studies , Safety , Triglycerides/blood
18.
Metabolism ; 43(3): 270-8, 1994 Mar.
Article in English | MEDLINE | ID: mdl-8139473

ABSTRACT

Lipoprotein abnormalities, mainly high very-low-density lipoprotein (VLDL) and low high-density lipoprotein (HDL) levels, increase the risk of coronary heart disease (CHD) in type II diabetic patients. To investigate the relationship between these lipoprotein abnormalities and the postprandial (PP) lipid-clearing capacity, triglyceride (TG) and hormonal levels were determined hourly up to the 4th hour after a mixed meal containing 32.5 g lipids/m2 body surface in 14 treated non-obese type II diabetic patients with adequate nutritional and glycemic control (hemoglobin A1C [HbA1C] < 7%) and in 12 healthy subjects matched for age, sex, and body mass index (BMI). Mean cholesterol levels did not differ between patients and controls, with fasting TG moderately increased in diabetics (140 +/- 70 v 66 +/- 34 mg/dL, P < .01). Whereas fasting TG levels in patients showed a continuous distribution from 55 to 250 mg/dL, postprandial TG clearly identified two different subgroups. A "high-responder" or hypertriglyceridemic subgroup (HTG) showed PP TG levels significantly higher than control levels (290 +/- 62 v 106 +/- 41 mg/dL, P < .001), with higher fasting TG as well (181 +/- 52, P < .01), whereas both fasting and PP TG levels were not different from control levels in the normotriglyceridemic (NTG) diabetic subgroup. The magnitude of the PP triglyceridemic area showed a negative correlation with HDL2 cholesterol (r = .66, P < .001) and a positive correlation with PP HDL2 TG enrichment (r = .80, P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
C-Peptide/blood , Diabetes Mellitus, Type 2/blood , Eating/physiology , Glucagon/blood , Hyperlipidemias/blood , Lipoproteins/blood , Adult , Apolipoproteins B/analysis , Body Mass Index , Fasting/physiology , Female , Humans , Insulin/blood , Lipids/blood , Lipoproteins, HDL/blood , Lipoproteins, LDL/blood , Male , Middle Aged , Triglycerides/blood
19.
Metabolism ; 41(5): 498-503, 1992 May.
Article in English | MEDLINE | ID: mdl-1588829

ABSTRACT

This multicenter, double-blind, randomized study was designed to compare the effects of simvastatin (20 mg/d and 40 mg/d) and fenofibrate (400 mg/d) on plasma lipids, lipoproteins, apolipoproteins (apo), and lipoprotein particles defined by their apo composition (Lp A-I, Lp A-II:A-I, Lp E:B, Lp C-III:B) in primary hypercholesterolemia. After 6 and 10 weeks of therapy, both drugs lowered plasma cholesterol, low-density lipoprotein (LDL) cholesterol, and apo B. The effect on LDL and apo B was significantly more pronounced for simvastatin (P = .01). Simvastatin increased Lp A-I, but did not change Lp A-II:A-I, while fenofibrate decreased Lp A-I and increased Lp A-II:A-I. Lp E:B and Lp C-III:B were decreased with both drugs, but fenofibrate was significantly more effective in reducing these particles than simvastatin. This study demonstrates that both drugs have beneficial effects on the parameters positively or negatively correlated with the atherosclerotic risk, with simvastatin being more effective in reducing some of them. These results suggest that the drugs led to different structural modifications of the lipoproteins, which would not be revealed by examination of lipoprotein density classes. These differences are probably related to the different mechanisms of action of the agents.


Subject(s)
Apolipoproteins/blood , Fenofibrate/therapeutic use , Hypercholesterolemia/drug therapy , Lipoproteins/blood , Lovastatin/analogs & derivatives , Adolescent , Adult , Aged , Anticholesteremic Agents/therapeutic use , Cholesterol/blood , Female , Humans , Hypercholesterolemia/blood , In Vitro Techniques , Lovastatin/therapeutic use , Male , Middle Aged , Simvastatin
20.
Pancreas ; 13(1): 96-9, 1996 Jul.
Article in English | MEDLINE | ID: mdl-8783340

ABSTRACT

The association between acute pancreatitis and severe hypertriglyceridemia has long been recognized. We report two cases of severe primary hypertriglyceridemia (types 1 and V) with recurrent acute pancreatitis. In both patients, observance of appropriate diet and drug therapy was insufficient. Recurrent episodes of pancreatitis were precipitated by dietary fat or alcohol abuse. A plasmapheresis was performed every 4 weeks to decrease the incidence of pancreatitis. It appears that plasmapheresis is a safe and highly effective method for quickly removing serum triglycerides. Moreover, plasma-pheresis may be useful for preventing acute pancreatitis.


Subject(s)
Hypertriglyceridemia/complications , Hypertriglyceridemia/therapy , Pancreatitis/prevention & control , Plasmapheresis , Acute Disease , Adult , Cholesterol/blood , Female , Humans , Hyperlipoproteinemia Type I/blood , Hyperlipoproteinemia Type I/complications , Hyperlipoproteinemia Type I/therapy , Hyperlipoproteinemia Type V/blood , Hyperlipoproteinemia Type V/complications , Hyperlipoproteinemia Type V/therapy , Male , Pancreatitis/etiology , Recurrence , Triglycerides/blood
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