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Biomedical subjects

P Barter

Publications and source records attributed to P Barter.

12 recordsLinked to original sources
PubMed2002

Treatment of dyslipidaemia in high-risk patients: too little, too late.

Evidence that lowering low-density cholesterol (LDL-C) reduces coronary events and mortality is now overwhelming and is reflected in treatment guidelines from around the world. The Joint European Guidelines recommend an LDL-C goal of <3.0 mmol/l in high-risk subjects. The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP)-III guidelines suggest an even more aggressive approach in high-risk individuals, with a recommended LDL-C goal of <2.6 mmol/l. Large numbers of high-risk patients are still not achieving the more conservative goals recommended in the Joint European Guidelines, let alone the more aggressive LDL-C target recommended in the new NCEPATP-III guidelines. The recognition in the NCEP ATP-III guidelines that a high-density lipoprotein cholesterol (HDL-C) level <1.0 mmol/l represents an important risk factor highlights the emergence of HDL-C as a key player in the genesis of coronary heart disease (CHD) and as a potential target for therapy. This may be especially important in people with insulin resistance with or without type 2 diabetes. There is evidence from the Helsinki Heart Study and the more recent Veterans Affairs HDL Intervention Trial (VA-HIT), both of which used gemfibrozil as the active agent, that the observed reduction in coronary events was correlated with the magnitude of the increase in HDL-C. The challenge for future management of high-risk individuals will be not only to reduce the level of LDL-C to below 2.6 mmol/l but also to increase HDL-C to levels above 1.0 mmol/l.

Anticholesteremic Agents↗
PubMed1997

A comparative study of the efficacy of simvastatin and gemfibrozil in combined hyperlipoproteinemia: prediction of response by baseline lipids, apo E genotype, lipoprotein(a) and insulin.

Combined hyperlipoproteinemia (CHL) can be difficult to treat because of the heterogeneous nature of the lipoprotein abnormalities. We compared the relative efficacies of simvastatin and gemfibrozil and sought predictors of responsiveness in terms of the baseline lipids and other potential metabolic determinants (plasma insulin, Lp(a) and apo E genotype). Sixty-six subjects entered a cross-over, randomized trial involving 12 weeks on each drug. Efficacy was assessed after 6 and 12 weeks on each treatment. Simvastatin lowered total cholesterol 24%, triglycerides 12%, LDL cholesterol 33%, raised HDL cholesterol 13% and substantially reduced the cholesterol:triglyceride ratio in VLDL and IDL. Gemfibrozil lowered total cholesterol 5%, triglycerides 44%, raised HDL 26% and reduced VLDL and IDL lipids more than simvastatin did. LDL size increased with both treatments and HDL size increased with simvastatin. Responsiveness (25% fall in cholesterol or 40% fall in triglycerides) was shown by 31/61 subjects when taking simvastatin (cholesterol-lowering) and by 44/60 taking gemfibrozil (triglyceride-lowering). Responsiveness was greatest in those with apo E2 genotype with both drugs (P < 0.05). Unexpectedly, responders to simvastatin tended to have lower baseline total cholesterol but higher triglyceride levels than those whose cholesterol or triglyceride was lowered by gemfibrozil. Nevertheless, more hypercholesterolemic subjects responded to simvastatin and more hypertriglyceridemic subjects to gemfibrozil. Lp(a) (P = 0.04) and plasma insulin concentrations (P = 0.03) were negative predictors of percentage triglyceride-lowering with gemfibrozil. The difference between the two drugs in triglyceride-lowering lessened with rising insulin and falling HDL cholesterol. Thus, the responsiveness to the two major classes of lipid lowering drugs can be partly predicted from baseline lipids and related metabolic parameters.

Anticholesteremic Agents↗
PubMed1997

Regulation of leucocyte-endothelial interactions of special relevance to atherogenesis.

1. The cellular events underlying atherosclerosis include the accumulation of lipid-laden monocytes in the neointima. This process is associated with the expression of adhesion proteins and chemokines by the endothelium, in a manner similar to that seen after the administration of pro-inflammatory cytokines to endothelial cells. 2. The processes that limit endothelial responses to proinflammatory cytokines are, therefore, the subject of this paper. Evidence is presented that the cytokine TGF-beta exerts a tonic inhibitory influence on endothelial responses. Furthermore, the smooth muscle cells adjacent to endothelial cells have a similar effect to exogenous TGF-beta and this suggests that these two cells form a functional interactive unit. Finally, the atheroprotective lipid fraction, high-density lipoproteins (HDL), also inhibits endothelial activation. The mechanism of effect of HDL that appears separate from its traditional role in cholesterol transport may yield novel insights into atheroprotection.

Animals↗
PubMed1994

Cholesteryl ester transfer protein: its role in plasma lipid transport.

1. The cholesteryl ester transfer protein (CETP) is a hydrophobic glycoprotein which acts in plasma to redistribute cholesteryl esters and triglyceride between plasma lipoproteins. 2. CETP also plays an important role in determining the composition and particle size distribution of high density lipoproteins (HDL). 3. Activity of CETP may be regulated in four ways: By factors which influence the concentration of CETP in plasma; by the activity of CETP inhibitor proteins; by variations in the concentrations and compositions of donor and acceptor lipoproteins and by factors which influence the interaction of CETP with plasma lipoproteins. 4. The mechanism of action of CETP is uncertain. Two models have been proposed: (i) a shuttle model in which CETP physically transports lipids between lipoprotein particles and (ii) a ternary complex model in which CETP forms a bridge between two lipoprotein particles, enabling them to exchange lipids. 5. Evidence is accumulating that CETP may be a pro-atherogenic factor.

Animals↗
PubMed1994

Cholesterol and cardiovascular disease: basic science.

Cholesterol is a normal constituent of blood plasma and of cell membranes in every tissue of the body. It is transported in plasma as a component of lipoproteins. Increased concentrations of specific lipoprotein fractions, namely low density lipoproteins (LDL) and intermediate density lipoproteins (IDL), have been implicated both in vitro and in vivo as causes of atherosclerosis. The mechanism by which these lipoproteins initiate atherosclerosis is unknown, although there is growing evidence that it involves interactions between lipoproteins and cells within the artery wall, setting in train complex, reactions which lead ultimately to the fully developed lesions.

Arteriosclerosis↗
PubMed1991

Application of reversed-phase high-performance liquid chromatography to the separation of apolipoproteins A-IV, A-I and E from rat high-density lipoprotein.

Apolipoproteins A-IV, A-I and E from rat high-density lipoprotein (HDL) were successfully purified by reversed-phase high-performance liquid chromatography (RP-HPLC), using a method which we have previously developed for the separation of apolipoproteins A-IV, A-I and E from human lymph chylomicrons [T. Tetaz, E. Kecorius, B. Grego and N. Fidge, J. Chromatogr., 511 (1990) 147]. Since analytical-scale RP-HPLC indicated that the C apolipoproteins from rat HDL coeluted with both apo A-IV and apo A-I, delipidated rat HDL was first subjected to preparative-scale size-exclusion HPLC (HPSEC) on a Serva Si300 column, which effectively separated the C apolipoproteins from all but apolipoprotein E. Fractions from HPSEC which were enriched for apolipoproteins A-IV, A-I or E were directly applied to RP-HPLC on a TSK Phenyl-5PW column. This procedure yielded fractions containing apolipoproteins A-IV, A-I or E which were pure as assessed by N-terminal sequencing and silver staining of sodium dodecyl sulphate-polyacrylamide gels.

Animals↗
PubMed1986

Metabolism of high density lipoproteins by the perfused rabbit liver.

The role of the liver in the catabolism of high density lipoproteins (HDL) was examined in isolated perfused rabbit livers. Using 125I-labeled rabbit HDL the disappearance of labeled apolipoproteins from the perfusate was biphasic with 7% of the label removed after 20 min and a further 6% between 20 and 90 min. In contrast, with HDL labeled with [3H]cholesteryl esters 35% of label had been removed after 90 min. The effect of liver perfusion on HDL size and composition was further studied by recirculating rabbit HDL for 120 min. In control experiments HDL was incubated at 37 degrees C for 120 min with nonperfused media and with media that had been liver perfused. The added HDL was predominantly particles of 4.8-4.9-mm radius, and incubation with nonperfused and preperfused media produced no significant change in size. However, liver perfusion resulted in particles predominantly 4.2-4.3-mm radius. Hepatic perfusion also significantly reduced HDL cholesteryl ester composition as a percentage of lipoproteins mass from 13.3 +/- 2.2% in control incubations to 10.7 +/- 3.1% (p less than 0.001), and cholesteryl ester:protein mass ratio was reduced from 0.31 +/- 0.06 in control to 0.24 +/- 0.10 (p less than 0.001) after 120 min of liver perfusion. Thus interaction of rabbit HDL with rabbit liver results in smaller HDL particles significantly depleted of core cholesteryl esters.

Animals↗
PubMed1977

Metabolism of cholesteryl esters of very low density lipoproteins in the guinea pig.

Very low density lipoproteins from guinea pig plasma, endogenously labeled with 3H in both the esterified and free cholesterol moieties, were obtained from serum collected 20 hr after the intravenous injection of 3H-cholesterol into donor animals. When these lipoproteins were injected into recipient guinea pigs, the esterified 3H-cholesterol was rapidly cleared from the plasma; 24% was in the liver in 5 min and 54% in 15 min. A smaller fraction of the esterified cholesterol appeared in other plasma lipoprotein fractions, with 3H in the low density lipoproteins reaching a peak of 9%-18% of the injected esterified 3H-cholesterol between 30 and 60 min after the injection. The results indicate that most of the esterified cholesterol in very low density lipoproteins of guinea pig plasma is removed directly by the liver and a minor fraction is transferred to low density lipoproteins. The pattern of labeling of cholesteryl esters of high density lipoproteins in these experiments suggests that their low concentration in the guinea pig is accompanied by a rapid turnover rate.

Animals↗
PubMedDate not supplied

High density lipoprotein subpopulations in chronic liver disease.

Severe liver disease may be associated with a reduction in plasma concentration of high density lipoprotein and an impairment of plasma cholesterol esterification. These changes were confirmed in two patients with severe acute on chronic alcoholic liver disease. In five additional patients with biopsy-proven clinically compensated cirrhosis, there was minimal reduction in concentration of plasma cholesteryl esters; there was, however a reduction of the plasma high density lipoprotein concentration to only 48 to 66% of normal. The particle size distribution of high density lipoprotein in these five patients was determined by gradient gel electrophoresis. The high density lipoprotein2 subfraction was preserved. The high density lipoprotein3 subfraction, however, was markedly changed with a reduction in the normal particles of radius 4.3 m and an accentuation of smaller particles of radius 3.9 m; in two patients, these smaller particles were the major high density lipoprotein subpopulation. Further investigations of this finding of a distinctive distribution of high density lipoprotein subpopulations in patient with chronic liver disease may provide new insights into high density lipoprotein metabolism.

Adult↗