Biomedical subjects

L A Simons

Publications and source records attributed to L A Simons.

At least 73 records · Page 4Linked to original sources

PubMed1990

On the mechanism by which an ACAT inhibitor (CL 277,082) influences plasma lipoproteins in the rat.

CL 277,082 is an inhibitor of acyl-CoA: cholesterol acyltransferase (ACAT). The effects of this drug on lipoprotein metabolism have been examined in cholesterol-fed rats. An optimal dose of drug incorporated into the diet (0.1% w/w) for 7 days reduced plasma cholesterol by 48% and plasma triglycerides by 72%. The decrease in plasma cholesterol was due to a reduction in triglyceride-rich lipoproteins and in HDL cholesterol. There was a significant 72% reduction in intestinal ACAT activity, accompanied by a 41% reduction in hepatic cholesterol content. There was a smaller 21% reduction in hepatic ACAT activity. Hepatic HMG-CoA reductase activity increased 3-fold. HDL binding activity by liver membranes was not altered significantly. The decrease in plasma cholesterol with this ACAT inhibitor is most likely due to decreased absorption of dietary cholesterol resulting from inhibition of intestinal ACAT.

Analysis of Variance↗

PubMed1990

Effects of an ethyl ester preparation of fish oils (Himega) on lipids and lipoproteins in hyperlipidaemia.

Clinical trials were conducted to assess the utility of HimegaR in the management of hyperlipidaemia. Himega is an ethyl ester concentrate from fish oil containing at least 50% n-3 fatty acid and minimal cholesterol. In Study 1, 13 subjects with primary hypertriglyceridaemia consumed Himega or a triglyceride-based fish oil in a randomised, double-blind crossover study for 12 weeks. Nine subjects took 2 g/day of n-3 fatty acid but four subjects with marked hypertriglyceridaemia took 4 g/day. Plasma triglycerides were reduced by approximately 50% with either product. There was a very similar effect on all lipid and lipoprotein parameters, including an 18% increase in LDL cholesterol and 23% increase in serum apolipoprotein B. In Study 2, nine subjects with primary hypercholesterolaemia took 2 g/day of n-3 fatty acid (Himega) or placebo (olive oil) in a randomised, double-blind crossover study for nine weeks. Plasma cholesterol was reduced by 6%, without significant change in LDL cholesterol. Fish oils in the form of ethyl esters or triglyceride are assimilated to a similar degree and lead to equivalent triglyceride-lowering in hypertriglyceridaemia, while simultaneously increasing LDL particle numbers. Himega does not reduce LDL levels in hypercholesteraemia, despite being a product with minimal cholesterol content.

Adult↗

PubMed1990

The Dubbo study: an Australian prospective community study of the health of elderly.

The proportion of Australian population over 60 years has risen progressively over the last 40 years and this growth is projected to continue. Major health problems of the elderly include coronary heart disease, cerebro-vascular disease, osteoporosis and fracture. The risk factors for coronary heart disease and stroke in middle-aged subjects have been extensively documented in prospective studies in Australia and elsewhere, and include lipid disorders, hypertension, cigarette smoking, diabetes and family history. Few prospective studies have been targeted exclusively on the elderly and information available with respect to vascular risk factors is fragmentary and contradictory. This is the background to a new prospective study of the health of elderly Australians now under way in Dubbo, NSW. The goals of the Dubbo Study are to identify predictors of mortality, hospitalisation and placement in long-term care, while specific aims are the study of risk factors for chronic diseases and disability. This report describes the study rationale, reasons for selecting Dubbo as the study site, methods and measures, participation rates and demography. The target population included all non-institutionalised subjects 60 years and over, domiciled in Dubbo, and is comprised of 1693 males and 2167 females. The attendance rate for an extensive medical and sociological baseline assessment over a 13 months' period was 73% for both sexes. The prospective study is now in place and within three to five years will be generating definitive information in the elderly.

Aged↗

PubMed1990

Impact of intensive educational approach to dietary change in NIDDM.

The aim of this study was to compare the effects of an intensive educational approach incorporating longer time, greater simplicity, repetition, and cognitive motivational techniques with a conventional one in subjects with established non-insulin-dependent diabetes mellitus (NIDDM) whose weight, glycemic control, and diet were not optimal. Subjects were randomly allocated to intensive or conventional education. Of 350 subjects, 70 met the study criteria, which included established NIDDM (greater than or equal to 3 mo), suboptimal recent glycemic control, dietary fat intake greater than or equal to 35% of total energy intake, and body mass index greater than or equal to 25 kg/m2. The intensive approach was associated with significantly greater improvements in dietary compliance, dietary intake (complex carbohydrate, [P = 0.013], legumes [P less than 0.0001], fiber [P less than 0.0001], total fat [P less than 0.004], saturated fat [P less than 0.004]), and total cholesterol level (P = 0.007). The transient improvement in glycemic control was similar in both groups. An intensive education program can improve dietary compliance in established NIDDM subjects more than a conventional one. These recommended dietary improvements achieve better improvement in total cholesterol but do not necessarily improve glycemic control.

Aged↗

PubMed1990

The effects of adrenergic blockade on lipoproteins using the rat as an experimental model.

Adrenergic blocking drugs are known to have adverse effects on lipids and lipoproteins in man, although the mechanisms underlying these effects are unclear. In order to see whether the rat might be a suitable model to explore this issue, adrenergic blockers having differing properties with respect to receptor interaction were administered to rats orally over seven days, followed by measurement of plasma lipids and lipoproteins. Total plasma cholesterol was not significantly influenced by any of the drugs used, while triglycerides were reduced by 20% and 31% respectively with pindolol and prazosin. With respect to changes in HDL cholesterol, it was found that: (a) HDL cholesterol was significantly reduced by 8% during combined beta 1, beta 2 blockade with propranolol; (b) HDL cholesterol was not significantly changed during selective beta 1 blockade using atenolol, or during combined beta 1, beta 2 blockade and partial beta 2 stimulation using pindolol; and (c) HDL cholesterol was significantly increased during combined beta 1 blockade and beta 2 stimulation using celiprolol by 12%, or during alpha 1 blockade with prazosin by 8%. It appears that beta 2 receptor exposure or stimulation may be one of the key points in the interaction between adrenergic blockade and lipoprotein metabolism.

Adrenergic beta-Antagonists↗

PubMed1989

Epidemiologic considerations in cardiovascular diseases in the elderly: international comparisons and trends.

As developed countries experience an "aging" of their populations, concern over cardiovascular disease, an important cause of death in the elderly, has grown. Improvements in the mortality rates of ischemic heart disease have been observed over the last 10 or 15 years in many nations, including Australia, the United States, Canada and Belgium. In other countries, mortality rates have remained unchanged and in some Eastern European countries, mortality rates have increased. In most instances where mortality rates have decreased, the reduction has been observed in both genders and has occurred across a wide age grouping, even in those aged 75 years and older. Truly representative data on risk factors for cardiovascular disease in the elderly are difficult to find; a new study has commenced in Australia and may provide more information.

Adult↗

PubMed1989

Platelet activation by oxidatively modified low density lipoproteins.

Interactions between altered lipoproteins and platelets may be important in atherosclerosis lesion formation and thrombosis. The aims of this study were to compare the effects of oxidatively modified and native low density lipoproteins (LDL) and high density lipoproteins (HDL) on platelet responses in the presence and absence of other platelet agonists, and investigate the mechanism(s) by which lipoproteins influence platelet activation. We have shown that native and oxidatively modified lipoproteins differ importantly in their effects on platelets; oxidation renders lipoproteins more reactive to platelets. Native LDL promote aggregation of human platelets, enhance the mobilization of arachidonate from phospholipids, increase thromboxane B2 production, and decrease membrane fluidity. Oxidized LDL are more reactive than native LDL and alone cause aggregation. Native HDL inhibit platelet responses and increase membrane fluidity. Oxidized HDL promote aggregation and cause spontaneous aggregation. The enhanced platelet responses cannot be attributed to increased production of thromboxane A2 since cyclooxygenase inhibitors (aspirin, indomethacin) have little inhibitory effect. The data suggest that activation of platelets by lipoproteins results from changes in membrane fluidity. These observations shed new light on the potential role of altered lipoproteins in the pathogenesis of atherosclerosis and its complications.

Arachidonic Acids↗

PubMed1989

Effects of fish oil supplementation on glucose and lipid metabolism in NIDDM.

Fish oils, containing omega-3 fatty acids (omega 3FAs), favorably influence plasma lipoproteins in nondiabetic humans and prevent the development of insulin resistance induced by fat feeding in rats. We studied the effects of fish oils in 10 subjects (aged 42-65 yr) with mild non-insulin-dependent diabetes mellitus (NIDDM). Subjects were fed a standard diabetic diet plus 1) no supplementation (baseline), 2) 10 g fish oil concentrate (30% omega 3FAs) daily, and 3) 10 g safflower oil daily over separate 3-wk periods, the latter two supplements being given in radom order by use of a double-blind crossover design. At the end of each diet period, fasting blood glucose (FBG), insulin, and lipids were measured, and insulin sensitivity was assessed with a hyperinsulinemic-euglycemic clamp performed with [3-3H]glucose. FBG increased 14% during fish oil and 11% during safflower oil supplementation compared with baseline (P less than .05), whereas body weight, fasting serum insulin levels, and insulin sensitivity were unchanged. The absolute increase in FBG during each supplementation period correlated with the baseline FBG (fish oil, r = .83, P less than .005); safflower oil, r = .75, P = .012). Fasting plasma triglyceride levels decreased during fish oil supplementation in the 4 subjects with baseline hypertriglyceridemia (greater than 2 mM) but were not significantly reduced overall. There was no significant change in fasting plasma total, high-density lipoprotein, and low-density lipoprotein cholesterol levels. In summary, dietary fish oil supplementation adversely affected glycemic control in NIDDM subjects without producing significant beneficial effects on plasma lipids. The effect of safflower oil supplementation was not significantly different from fish oil, suggesting that the negative effects on glucose metabolism may be related to the extra energy or fat intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Glucose↗

PubMed1988

Familial aggregation of coronary heart disease: partial mediation by high density lipoproteins?

The potential explanation of coronary heart disease inheritance by the major coronary risk factors was explored in a random sample of 1044 males, aged 40-70 years, who formed part of the Jerusalem Lipid Research Clinic Prevalence Study. Standardised data were available on personal and family history, coronary risk factors, resting and exercise electrocardiography. Twelve percent of subjects had coronary heart disease (previous myocardial infarction or electrocardiographic changes) and 20% had a family history of heart attack before 60 years in first degree relatives. In the presence of a family history of heart attack, the mean level of high density lipoprotein-cholesterol (HDL-C) was 5 mg/dl lower in cases of coronary heart disease than in controls. No such difference existed in the absence of a family history of heart attack. In multiple logistic regression, HDL-C was a significant negative predictor of coronary heart disease presence, but only in subjects having a positive family history. A 1 standard deviation (10 mg/dl) increment in HDL-C was associated with a two-thirds reduction in heart disease risk. Other risk factors did not predict the occurrence of coronary heart disease to any significant extent in subjects with a positive family history of heart attack. In an overall logistic model combining family history with other risk factors, the significant predictors of heart disease were: age, total plasma cholesterol, hypertension, family history and HDL-C. The interaction term, family history X HDL-C, was also a significant negative predictor of heart disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1987

Effects of MK-733 on plasma lipid and lipoprotein levels in subjects with hypercholesterolaemia.

MK-733, which is a competitive inhibitor of the rate-limiting step in cholesterol biosynthesis, or a matching placebo was administered to 30 subjects with primary hypercholesterolaemia (who were already receiving dietary treatment) over a period of four weeks in a double-blind trial. Twenty-one subjects manifested heterozygous familial hypercholesterolaemia and nine subjects had polygenic hypercholesterolaemia. Five subjects received placebo, 15 subjects a low dose of MK-733 (2.5-10 mg/day) and 10 subjects received a high dose of MK-733 (20-80 mg/day). Plasma cholesterol levels in subjects who were receiving MK-733 declined significantly and in a dose-dependent fashion (31% reduction in plasma cholesterol levels with a high dose, 19% reduction with a low dose). Eight of 10 subjects who were receiving a high dose of MK-733 achieved better than a 30% reduction in plasma cholesterol levels after four weeks of treatment. The response was independent of the presence or absence of familial hypercholesterolaemia. High-density lipoprotein cholesterol levels did not change significantly, but there was a suggestive, dose-dependent reduction in plasma triglyceride levels after four weeks of treatment. MK-733 was well-tolerated, appeared to be safe, and may ultimately become an important drug in the management of more severe grades of hypercholesterolaemia.

Adult↗

PubMed1987

Coronary risk factors six to 12 months after coronary artery bypass graft surgery.

Hyperlipidaemia appears to be a major factor in the development of graft atherosclerosis in the five- to 10-year period after coronary artery bypass graft surgery. A preliminary survey of coronary risk factors was conducted in 103 consecutive patients, who lived in the Sydney metropolitan area and who had undergone coronary artery bypass graft surgery six to 12 months previously in a single hospital unit. The information was collected by reply-paid questionnaire (response rate, 93%) and by clinical assessment (measurement rate, 85%). The group was predominantly (86%) male and elderly (mean age, 62 years; 60% of men and 85% of women were aged over 59 years). Seven per cent of the group had undergone a second operation. Approximately two of every three subjects manifested hypercholesterolaemia, one in four subjects manifested hypertension and one in three subjects was overweight, but only one in 20 subjects currently smoked cigarettes. The findings were compared with those in a general population sample; the assumption was made that coronary risk factors would be overrepresented in a sample of patients in whom coronary artery bypass graft surgery had been required. The data suggested that cigarette smoking was receiving appropriate intervention (before or after surgery), that hypertension was receiving some intervention, and that hyperlipidaemia was receiving insufficient intervention. On a purely empirical basis, the appropriate use of a cardiac rehabilitation service is suggested as one possible way of preventing the return of a large number of patients with graft atherosclerosis in later years.

Adult↗

PubMed1987

Chylomicrons and chylomicron remnants in coronary artery disease: a case-control study.

Epidemiologic studies of coronary artery disease have largely overlooked the role of triglyceride-rich lipoproteins circulating in the post-prandial state. We have conducted a case-control study in males which examined fasting plasma lipoproteins and lipoproteins circulating 4 h after ingestion of a test meal containing fat and cholesterol. The cases were 82 subjects with coronary artery disease confirmed by angiography, while there were two control groups: one group of 38 'hospital controls' free of significant coronary disease by angiography, and a second group of 61 'workforce controls' free of coronary disease on historical grounds. Mean plasma and LDL cholesterol levels were significantly higher and HDL cholesterol levels were significantly lower in cases than in controls. The apo-B48/apo-B100 ratio in lipoproteins Sf greater than 60 obtained 4 h post-prandially, a relative measure of chylomicron and remnant presence, was significantly higher in cases than in controls. After pooling of all data, the prevalence of coronary artery disease was found to increase progressively with the concentration of plasma cholesterol and triglycerides, total cholesterol/HDL cholesterol ratio and the apo-B48/apo-B100 ratio in Sf greater than 60, the relative risk being highest for total cholesterol/HDL cholesterol ratio. After controlling for the confounding effects of age and other lipid factors via multiple logistic regression, apo-B48/apo-B100 ratio was still a significant predictor of coronary artery disease presence (z = 1.97, P less than 0.05) in a 'dose-response' fashion. The risk of coronary artery disease in the top quartile of apo-B48/apo-B100 distribution was 2.2-fold greater than that for the bottom quartile, after adjustment for the effects of other risk factors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1987

Maintenance of plasma triglyceride-lowering through use of low-dose fish oils in the diet.

The ingestion of large doses of fish oil may be associated with a marked reduction in plasma triglyceride concentrations. The present study was a preliminary evaluation of whether a lower maintenance dose of fish oils in hyperlipidemic patients would be sufficient to sustain therapeutic effects already achieved on higher dosage over a prior period of three months or longer. For the purposes of this study, 10 or 16g/day of fish oil (LipitacR) was defined as high dosage, 6g/day as medium dosage and 3g/day as low dosage. Five subjects entered on high dosage and were subsequently evaluated on medium and then on low dosage at intervals of six weeks. Five subjects entered on medium dosage and were evaluated after six weeks on low dosage. Seven of the subjects entered with a significant degree of hypertriglyceridemia while the remainder had hypercholesterolemia. Subjects entering with background triglyceride concentrations in excess of 2mmol/l showed reduced triglyceride concentrations at all dose levels, while two subjects with entry triglycerides in excess of 10mmmol/l experienced further improvement in plasma triglycerides when comparing medium with low dosage, or high with medium dosage. Low dose fish oil appears to have potential as a form of maintenance therapy in the management of moderate degrees of hypertriglyceridemia.

Adult↗

PubMed1986

Education level and coronary risk factors in Australians.

There is an inverse association between social class ranking and mortality from coronary heart disease in Australia and in some other countries. To explain whether this association is related to differences in risk factors, the relationship between coronary risk factors and the highest level of education completed was explored for a reasonably representative cross-section of the adult Australian population. After adjustment for the effects of age, relative weight and alcohol intake, blood pressure was found to vary inversely with education level in both sexes. In men only plasma cholesterol, triglycerides and high density lipoprotein cholesterol levels showed no significant variation with education level. In women, plasma triglycerides and high density lipoprotein cholesterol levels varied inversely with education level after adjustment. There was less cigarette smoking among more highly educated men but no clear smoking trends among women. The findings broadly confirm the results of similar analyses which used occupation as the measure of social class and have implications for future community education programmes in that present strategies may be inappropriate for less highly-educated members of society.

Alcohol Drinking↗

PubMed1986

Interrelations of lipids and lipoproteins with coronary artery disease mortality in 19 countries.

Coronary risk factors differ in importance from country to country, but a proportion of interpopulation differences in coronary artery disease (CAD) mortality is probably closely related to interpopulation differences in total serum cholesterol levels. Interpopulation differences in high density lipoprotein (HDL) cholesterol levels supposedly do not explain interpopulation differences in CAD mortality, although HDL cholesterol may be an important negative risk factor within a population. Age- and sex-specific serum cholesterol, triglyceride and HDL cholesterol levels have been sought for 27 industrialized countries for which the World Health Organization has reliable mortality data. At least partially complete information was obtained from 19 countries, derived from national or regional studies in middle-aged subjects, and this has been related to CAD mortality rates. In men, 45% of the interpopulation variation in CAD mortality was explained by variation in serum cholesterol levels; 32% by variation in HDL cholesterol; and 55% by variation in the ratio of total serum cholesterol/HDL cholesterol. CAD mortality in men did not correlate with a population's serum triglyceride levels. In women, the only significant correlate of interpopulation variation in CAD mortality was the ratio of total serum cholesterol/HDL cholesterol, which explained 31% of the variation in CAD mortality. These findings highlight the contributions of total serum cholesterol and the ratio of total serum cholesterol/HDL cholesterol to CAD mortality in men at the international level and have implications for individual members of a population. Similar analyses in women were not particularly informative.

Adult↗

PubMed1986

Quantification of LDL cholesteryl ester contribution to biliary steroids in the rat.

The proportion of LDL cholesteryl ester converted to biliary steroids was quantified in the rat. The pre-existing pool of bile was allowed to drain for 10-12 h through a bile duct cannula. A single intravenous pulse injection of LDL labelled with [3H]cholesterol linoleyl ester was made, followed by a constant infusion of the same material in order to maintain constant specific radioactivity in plasma. A new steady state was achieved within 6 h and bile samples were then collected hourly until 12 h. Although substantial amounts (53-61 micrograms/h) of cholesteryl ester were released into the liver during LDL catabolism, only a very small fraction (0.8-1.90 micrograms/h) was found in biliary steroids. The proportion of LDL cholesteryl esters contributing to biliary steroids was only 1-2%. These results perhaps explain why perturbations to accelerate bile acid excretion have no effect on plasma LDL cholesterol concentration in the rat.

Animals↗

PubMed1986

Regulation of low-density-lipoprotein metabolism in the rat.

The mechanism of regulation of plasma low-density-lipoprotein (LDL) metabolism in the rat was studied under a number of experimental conditions. LDL clearance and uptake in the liver was measured after intravenous pulse injection of [14C]sucrose-labelled LDL alone or in combination with reductively methylated [3H]sucrose-labelled LDL. Hyperthyroid rats showed a significant increase in fractional catabolic rate (FCR) and the proportion of LDL degraded in the liver, whereas the synthetic rate of LDL increased by 50%. Receptor-mediated clearance increased 2-fold. Hypothyroid rats showed a significant increase in LDL concentration. The FCR and proportion of LDL degraded in the liver were decreased significantly. Receptor-mediated clearance was also reduced. Cholesterol feeding increased chylomicron, very-low-density-and intermediate-density-lipoprotein cholesterol concentrations, but there was no change in the LDL concentration, FCR or the synthetic rate of LDL. Cholestyramine feeding did not induce changes in the kinetic parameters. These results indicate that, in the rat, the hepatic LDL-receptor pathway is under hormonal control, whereas cholesterol and cholestyramine feeding have no demonstrated effect on LDL metabolism.

Animals↗

PubMed1986

Effects of Ro 16-0521 on cholesterol metabolism in the rat.

Ro 16-0521 is a newly synthesized benzodiazepine derivative which is devoid of reactivity with the brain benzodiazepine receptor. The effects of this drug on plasma lipids and lipoproteins and hepatic cholesterol metabolism have been examined in the cholesterol-fed rat. Drug therapy was associated with dose-related falls in plasma cholesterol concentration, liver cholesterol content, and the activity of the liver enzyme Acyl-CoA cholesterol acyltransferase. Drug therapy abolished the lipid and lipoprotein changes induced by cholesterol feeding, including those associated with a diet supplemented with olive oil to facilitate cholesterol loading. Drug therapy was also associated with an increased activity of the enzyme HMG-CoA reductase and reduced hepatic microsomal cholesterol content. It is suggested that the cholesterol-fed rat will be a suitable model for further mechanistic studies.

Animals↗