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Biomedical subjects

W V Brown

Publications and source records attributed to W V Brown.

At least 55 records · Page 3Linked to original sources
PubMed1990

Clinical trials including an update on the Helsinki Heart Study.

The incidence of myocardial infarction (MI), sudden death and other clinical manifestations of coronary heart disease can be reduced by lowering the blood cholesterol level. This is now well established by multiple clinical trials using a variety of interventions including diet and lipid-lowering drugs. Dietary studies in Los Angeles and in Oslo, Norway, have induced a reduction in blood cholesterol of between 10 and 15% with correlated reductions in coronary disease of 20 to 50%. Both niacin and clofibrate in separate cohorts demonstrated a significant reduction in new MI during 5 years of treatment in the Coronary Drug Project. Similar reductions in new MI occurred in the World Health Organization Study with clofibrate. However, in this trial and different from all other trials, mortality in the drug-treatment group actually increased. This finding remains unexplained. In the more recent Lipid Research Clinics Coronary Primary Prevention Trial using the bile acid-binding resin cholestyramine, only a 9% reduction in total cholesterol resulted in a highly significant reduction in the major end points--MI and sudden death--as well as in other secondary end points, including the need for coronary artery bypass graft surgery, ischemic changes on exercise electrocardiography and new-onset angina. Recently, another primary prevention trial using gemfibrozil produced a similar reduction in total cholesterol but a much more significant increase in high-density lipoprotein cholesterol. The reduction in coronary heart disease was in excess of 34% and was strongly related to both low-density lipoprotein cholesterol reduction and high-density lipoprotein elevation. Combination drug studies have produced larger reductions in total cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Structure and polymorphic map of human lipoprotein lipase gene.

Lipoprotein lipase (LPL) catalyzes the key step for the removal of triacylglycerol-rich lipoproteins from the circulation. In this paper, we report the cloning and structure of the normal human LPL gene, which was isolated in three overlapping lambda phage clones that span about 35 kilo bases (kb) of the genetic locus. The peptide coding region of the gene is approx. 23 kb in length and contains nine exons with intron sizes ranging from 0.7 to 8.7 kb. The entire 3' untranslated region is in the tenth exon. Specific sequences in this region support the hypothesis that two mRNA species found for human LPL are generated by differential utilization of polyadenylation signals. The first exon occurs in the 5' untranslated region and the region coding for the signal peptide. The second exon includes the protein domain coding for the N-linked glycosylation site that is required for the expression of enzyme activity. The fourth exon contains the region that was proposed as a lipid binding domain, the sixth for one putative heparin binding domain, and the eighth codes for a domain containing another N-linked glycosylation site. These results suggest that the unique structural and functional domains are confined to specific exons. The PvuII polymorphic site was located within the intron between exon 6 and 7 and the HindIII polymorphic site to the 3' flanking region. The location of these polymorphic sites suggests that the PvuII restriction fragment length polymorphism (RFLP) associated with lipase deficiency in a few Japanese kindred may be a linkage marker for a functional defect of LPL, while the HindIII RFLP associated with hypertriglyceridemia may be important for gene regulation of LPL.

Amino Acid Sequence↗
PubMed1990

Efficacy and safety of pravastatin in patients with primary hypercholesterolemia. I. A dose-response study.

This multicenter, double-blind, placebo-controlled, dose-response study was conducted in patients with primary hypercholesterolemia to examine the effects of pravastatin, a selective inhibitor of HMG-CoA reductase, on plasma lipids and lipoproteins. A total of 306 patients on cholesterol-lowering diets received twice daily doses of 5 mg, 10 mg, 20 mg pravastatin, or placebo for 12 weeks. Marked reductions in low density lipoprotein (LDL) cholesterol and total cholesterol were observed after 1 week of treatment; maximum lipid-lowering effects occurred at 4 weeks and were sustained for the duration of the trial. At week 12, pravastatin treatment resulted in dose-dependent mean reductions from baseline in LDL cholesterol of 17.5%, 22.9%, and 30.8% for the 3 doses tested (P less than or equal to 0001 compared with baseline and placebo). The reduction in LDL cholesterol was log-linear with respect to dose; each doubling of dose reduced LDL cholesterol an additional 6.5%. Dose-dependent reductions in total cholesterol from 12.9% to 23.3% also occurred (P less than or equal to 0.001). Triglycerides decreased by as 15.4% (P less than or equal to 0.001) and high-density lipoprotein (HDL) cholesterol increased approximately 7% (P less than or equal to 0.01), but these effects were not dose-dependent. No patient receiving pravastatin was discontinued during the 12-week trial. Transient episodes of rash and headache occurred. Slight increases in mean serum levels of ASAT and ALAT occurred, and 2% of both placebo- and pravastatin-treated patients reported myalgia although there was no clinically significant elevation of creatine kinase. These data indicate that pravastatin favorably affects all lipid parameters and is well tolerated.

Anticholesteremic Agents↗
PubMed1990

Review of clinical trials: proving the lipid hypothesis.

The Lipid Hypothesis, which states that lowering blood cholesterol levels should significantly reduce the incidence of coronary heart disease (CHD), has been repeatedly tested in primary and secondary intervention trials. Viewed as a whole, it is apparent that the incidence of CHD in treated groups decreased in proportion to the degree of plasma cholesterol reduction. An early study at the Wadsworth Hospital in Los Angeles showed that a diet high in polyunsaturated fat and low in cholesterol reduced the incidence of CHD. The Oslo study of diet and smoking intervention demonstrated a significant decrease in CHD concomitant with a 13% reduction in serum cholesterol achieved through a low saturated-fat diet and cessation of smoking. In the World Health Organization primary prevention trial, clofibrate reduced serum cholesterol by 9% and first clinical episodes of myocardial infarction by 20%. There was a 37% rise in total mortality, but no causal link with clofibrate has been found, and this was not significant when corrected for age at death. A secondary trial, the Coronary Drug Project, demonstrated that oestrogen and dextrothyroxine were clearly toxic. In this trial, niacin produced a 10% fall in serum cholesterol and mortality was 11% lower than in the placebo group after long-term follow-up. The Lipid Research Clinics-Coronary Primary Prevention Trial (LRC-CPPT) found an 8% reduction in plasma cholesterol and a 19% reduction in the incidence of CHD in the group treated with cholestyramine compared with placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Dietary recommendations to prevent coronary heart disease.

The evidence that limiting dietary saturated fat and cholesterol will lower LDL cholesterol and contribute to the reduction in risk of cardiovascular disease is adequate for sound dietary recommendations to patients and to the public at large. Reduction of intake of all saturated fats to less than 10% of calories is a practical and achievable goal for Western man. Further reduction to less than 7% of calories is possible with a motivated and well instructed patient. The mechanism by which saturated fatty acids, particularly palmitate and laurate raise LDL cholesterol need detailed biochemical and physiologic study. Dietary cholesterol is unnecessary and clearly contributes to vascular disease in Western man. This vascular effect appears to be only partially explained by its effect on LDL cholesterol. Reduction to less than 300 mg per day for men of average size is achievable. Women and those eating fewer calories should strive for even less. Monounsaturated fats (oleic acid) can be consumed at levels of 20% of calories without significant concern if total calories are within limits to maintain desirable weight. Omega-6 polyunsaturated fats do not offer a significant health concern and need not be limited below the current intake of 7% of calories in the United States. Populations eating higher levels should be monitored to determine if such intakes are associated with either improved health or long-term ill effects since this level of intake has not been a long-standing tradition in any known culture. Omega-3 fatty acids might be increased to 2 or 3% of calories with potential benefit. Eating fish and marine animals is the most clearly documented safe method for achieving this. Larger intakes and particularly the use of fish oil supplements is unproven therapy for vascular disease prevention and needs much further study as a medical treatment for a variety of disorders. Protein intake is more than adequate in the USA and further increases could have negative effects on the prevalence of renal disease and osteoporosis. Although these issues are of hypothetical interest at the moment, they are worthy of considerable investigation. Complex carbohydrates consumed as components of vegetables, fruits and grains should be considered proven safe and healthful. Increasing calories from these sources at the expense of saturated fats and simple sugars should prove highly beneficial to Western populations. Fiber from these sources may have beneficial effects on blood cholesterol and intestinal function. Soluble fiber is documented to lower LDL cholesterol but the mechanism of this effect is not established and is worthy of considerable study.(ABSTRACT TRUNCATED AT 400 WORDS)

Alcohol Drinking↗
PubMed1989

Expression of lipoprotein lipase gene in combined lipase deficiency.

The expression of the gene for lipoprotein lipase (LPL) was studied in brown adipose tissue and the liver of combined lipase deficient (cld/cld) and unaffected mice. The mRNA specific for LPL was detected in both animals. Although the size of LPL mRNA in cld mice was similar to that of unaffected mice, the mRNA concentration in affected animals was higher than in unaffected animals. We also studied the LPL gene mutation in cld mice by Southern blot analysis. No restriction fragment length polymorphisms were observed after digestion with 16 endonucleases. These data indicate that there is no gene insertion or deletion, but do not exclude the possibility of point mutation in the LPL structural gene. However, the present results agree with the hypothesis that the genetic defect in cld is not due to a mutation in the LPL structural gene, but instead involves the defective post-translational processing of LPL or defective cellular function affecting transport and secretion of this enzyme group.

Animals↗
PubMed1989

Interaction of lipoprotein lipase with heparin.

The hydrolysis of triglyceride-rich plasma lipoproteins is initiated by lipoprotein lipase (LPL) located at the luminal surface of endothelial cells. We previously reported that LPL binds to cultured endothelial cells with a Km of 2.7 x 10(-7) M and that this binding is inhibited by heparinase, heparin, or heparan sulfate. We and others recently isolated LPL cDNAs from various animals. The deduced amino acid sequence from cDNA sequence is highly conserved among animal species. The structural analysis revealed two regions rich in basic amino acid residues at the carboxyl-terminal region that may interact with the anionic heparin-like molecules. Amino acid residues 292 to 300 of bovine LPL are extremely similar to the reported heparin binding sites on apolipoproteins B-100 (amino acid residues 3359-3367) and E (amino acid residues 142-150).

Amino Acid Sequence↗
PubMed1989

Review of clinical studies of fenofibrate in combination with currently approved lipid-lowering drugs.

Recent trials have investigated the usefulness of fenofibrate, alone and in combination with other lipid-lowering therapies, in the treatment of hyperlipidemia. Studies of fenofibrate + bile acid sequestrants demonstrate that these two therapies may have an additive effect in reducing total cholesterol, low-density lipoprotein (LDL) cholesterol, very-low-density lipoprotein (VLDL) cholesterol and triglyceride levels in patients with hyperlipoproteinemia or familial hypercholesterolemia. These lipoprotein changes have been associated with a regression of tendon xanthoma. Pharmacokinetic studies have shown that bile acid sequestrants do not alter the absorption or the plasma levels of fenofibrate. The combined use of fenofibrate with bile acid sequestrants has been found to be comparably effective with the new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, synvinolin, with respect to the reduction of total cholesterol and LDL. Although synvinolin was more effective in lowering LDL, VLDL cholesterol and triglycerides were reduced to a greater extent with fenofibrate. Another notable difference was that fenofibrate + bile acids more markedly increased HDL levels. The combination of fenofibrate + nicotinic acid also appears to have a beneficial effect on lipoproteins. These preliminary results indicate that fenofibrate may be a useful addition to the present lipid-lowering drug armamentarium.

Anticholesteremic Agents↗
PubMed1989

Treatment of hypercholesterolaemia with fenofibrate: a review.

Hypercholesterolaemia is a metabolic disorder characterized by elevated total and LDL-cholesterol levels. Patients with hypercholesterolaemia are at high risk for coronary artery disease, and current guidelines recommend treatment for patients with elevated total or LDL-cholesterol levels. Fenofibrate is a fibric acid derivative that has been available in much of the world for over 10 years. In controlled and comparative clinical trials, fenofibrate has been shown to lower significantly plasma levels of total and LDL-cholesterol as well as plasma triglycerides. In addition, fenofibrate is associated with a relatively low incidence of adverse effects with some gastro-intestinal, dermatological and musculoskeletal reactions. Based on its efficacy and tolerability profile, fenofibrate would appear to be an appropriate choice for treatment of hypercholesterolaemia in selected patients.

Cholesterol↗
PubMed1988

Effect of lipoprotein lipase and hepatic triglyceride lipase activity on the distribution of apolipoprotein E among the plasma lipoproteins.

The independent roles of human lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) in determining the distribution of apolipoprotein E (apo E) among the plasma lipoproteins has been studied in vitro. In one series of three studies, postheparin plasma (10%) was incubated for 2 h with autologous plasma and the changes in the lipoprotein association of apo E after lipase exposure were determined after lipoprotein fractionation on 4% agarose columns. Specificity for LPL or HTGL was achieved by inhibition with goat anti-human HTGL or with 1 M NaCl, respectively. In another study, LPL and HTGL were partially purified from human postheparin plasma. The independent effects of these enzymes on the lipoprotein association of apo E were then examined after incubation of plasma in the absence or presence of one or both lipases. Data from both types of in vitro study showed that LPL-mediated triglyceride hydrolysis in the absence of HTGL activity was accompanied by a loss of apo E from triglyceride-rich lipoproteins, a gain or no change in the apo E-containing lipoproteins the size of intermediate density lipoproteins (IDL) and inconsistent changes in the apo E mass associated with high density lipoproteins (HDL). HTGL activity, on the other hand, in the absence of LPL, resulted in a redistribution of apo E from lipoproteins the size of IDL and a gain by those of HDL size. These studies thus support previous in vivo studies which pointed toward a specific role for HTGL in the processing of apo E containing IDL.

Apolipoproteins↗
PubMed1988

Focus on fenofibrate.

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Anticholesteremic Agents↗
PubMed1987

Effects of fenofibrate on plasma lipoproteins in hypercholesterolemia and combined hyperlipidemia.

To investigate the lipoprotein effect of fenofibrate in hypercholesterolemia or combined hyperlipidemia (types II A and II B hyperlipidemias, respectively), 240 patients were recruited and 227 randomized to a double-blind randomized trial lasting 24 weeks and 192 patients continued to participate in an open-label phase for another 24 weeks. A 100-mg dose of fenofibrate or a matching placebo was given three times daily. Fenofibrate side effects in excess of placebo affected 6 percent of fenofibrate users and were confined almost entirely to skin rashes. In 180 hypercholesterolemic patients randomly assigned to receive fenofibrate versus placebo, triglyceride and very low-density lipoprotein cholesterol levels decreased 38 percent, total cholesterol levels decreased 17.5 percent, and low-density lipoprotein cholesterol levels decreased 20.3 percent with fenofibrate treatment. High-density lipoprotein cholesterol levels increased 11.1 percent with a decrease in the low-density lipoprotein cholesterol: high-density lipoprotein cholesterol ratio of 27 percent. All differences were statistically significant (p less than 0.01). In combined hyperlipidemic (type II B) patients, triglyceride levels decreased by 45 percent, very low-density lipoprotein cholesterol levels decreased 52.7 percent, total cholesterol levels decreased 16 percent, low-density lipoprotein cholesterol levels decreased 6 percent, and high-density lipoprotein levels increased 15.3 percent for a low-density lipoprotein cholesterol: high-density lipoprotein cholesterol ratio decrease of 13 percent. All differences were again statistically significant (p less than 0.01). In both groups of patients, the onset of the drug effect was generally rapid, with maximal total and low-density lipoprotein cholesterol level lowering achieved within four weeks in hypercholesterolemic patients and maximal triglyceride and cholesterol level lowering in hypertriglyceridemic patients achieved in two weeks. Maximum high-density lipoprotein increases occurred after four weeks in type II A patients and 12 to 16 weeks in type II B patients. Fenofibrate is a well-tolerated drug in the fibric acid series and has putatively beneficial effects on triglyceride, very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein cholesterol concentrations in both type II A and type II B hyperlipidemic patients. If the lipid hypothesis of atherosclerosis applies to the lipoprotein changes induced by fenofibrate, reductions in cardiovascular disease risk in both type II A and II B hyperlipidemic patients should result from fenofibrate treatment.

Adult↗