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Biomedical subjects

P N Demacker

Publications and source records attributed to P N Demacker.

At least 91 records · Page 5Linked to original sources
PubMed1993

A 2-year study on the beneficial effects of 17 beta-oestradiol-dydrogesterone therapy on serum lipoproteins and Lp(a) in postmenopausal women: no additional unfavourable effects of dydrogesterone.

INTRODUCTION: Postmenopausal hormone replacement therapy (HRT) has been described to reduce the risk of developing cardiovascular disease (CVD), which can be attributed at least in part to beneficial effects of oestrogens on serum lipoproteins. Little is known about a possible counteracting effect by the progestogen integrated in modern HRT regimens. OBJECTIVE: To study the possible changes in serum lipids, lipoproteins and apolipoproteins during HRT with special emphasis on the possible progestational effect. STUDY DESIGN: In an open-label longitudinal non-comparative study 23 healthy non-hysterectomized postmenopausal women were treated with continuous micronized 17 beta-oestradiol, 2 mg daily, in combination with cyclic dydrogesterone, 10 mg daily, the first 14 days of each 28-day treatment cycle. The women were followed for up to 2 years. RESULTS: After 2 years serum total cholesterol and low-density lipoprotein cholesterol had decreased by 9.0% and 18%, respectively (P < 0.01), while high-density lipoprotein cholesterol had increased by 13% (P < 0.01). The latter change was accompanied with similar increases in apolipoprotein A-I (+16%; P < 0.01) and A-II (+13%; P < 0.01), while apolipoprotein B remained unchanged. Serum very low-density lipoprotein (VLDL) cholesterol and VLDL-triglycerides increased by 28% and 21%, respectively, the latter reflecting the slight increase in serum triglycerides by 21%. These values, however, remained within the normal range. Serum lipoprotein(a) decreased by 16% (P < 0.01). All calculated atherogenic indices decreased (P < 0.01) during the study period. Serum lipids and (apo)lipoproteins did not change after withdrawal of dydrogesterone for 14 days during the combination therapy in the last cycle studied. Serum fibrinogen decreased by 8.4% (P < 0.01) in the first 12 cycles, after which it increased to 13% above baseline value (P < 0.01 vs. baseline). Antithrombin III did not change and serum glucose decreased by 5.7%. CONCLUSIONS: This HRT regimen induces (and also when given for a longer period) beneficial changes in the lipid profile, without affecting important indicators of thrombosis. Also, the glucose metabolism does not seem to be interfered with. Cyclic administration of dydrogesterone does not unfavourably affect serum lipids and (apo)lipoproteins when combined with 17 beta-oestradiol supplementation. Therefore, this combination hormone regimen can be recommended for use in HRT.

Blood Coagulation Factors↗
PubMed1993

Plasma activities of lecithin:cholesterol acyltransferase, lipid transfer proteins and post-heparin lipases in inbred strains of rabbits hypo- or hyper-responsive to dietary cholesterol.

Plasma lipoproteins, plasma activities of lecithin:cholesterol acyltransferase (LCAT), phospholipid transfer protein (PLTP), cholesteryl ester transfer protein (CETP) and post-heparin lipases were measured before and after cholesterol challenge in two inbred strains of rabbits with either a high (hyper-responders) or a low (hyporesponders) response of plasma cholesterol to dietary cholesterol. The purpose of this study was to provide clues about the mechanisms underlying the effect of dietary cholesterol on lipoprotein levels and composition, and particularly those underlying the strain difference of this effect. Cholesterol feeding (0.15 g of cholesterol/100 g of diet) caused increased plasma total cholesterol concentrations and an increased ratio of cholesteryl esters:triacylglycerol in all lipoprotein particles in both strains; these effects were significantly greater in hyper- than hypo-responsive rabbits. Feeding on the high-cholesterol diet lowered plasma triacylglycerols in hyper-responders, but caused increased plasma triacylglycerol levels in hyporesponders. This was accompanied by significantly greater increases in the activities of hepatic triacylglycerol lipase and lipoprotein lipase in hyper- than in hypo-responders. Both strains showed a dietary-cholesterol-induced rise in plasma CETP as well as in PLTP activity. The increase in PLTP activity was greater in the hyper-responders, but that of CETP was less. There was no effect of dietary cholesterol on LCAT activity. It is hypothesized that the lipases are involved in the removal of cholesterol-rich lipoproteins.

Animals↗
PubMed1993

Circulating soluble tumor necrosis factor receptors, interleukin-2 receptors, tumor necrosis factor alpha, and interleukin-6 levels in rheumatoid arthritis. Longitudinal evaluation during methotrexate and azathioprine therapy.

OBJECTIVE: To assess whether circulating concentrations of soluble tumor necrosis factor receptors (sTNFR; p55 and p75), soluble interleukin-2 receptors (sIL-2R), tumor necrosis factor alpha (TNF alpha), and interleukin-6 (IL-6) reflect clinical response and whether changes are dependent on the drug used in rheumatoid arthritis (RA) patients taking methotrexate (MTX) or azathioprine (AZA). METHODS: These cytokines and soluble receptors were assessed in 20 control subjects and serially for up to 48 weeks in 61 RA patients, by bioassay (IL-6) and immunoassays (sTNFR, sIL-2R, TNF alpha, and IL-6). RESULTS: Concentrations of p55 and p75, sIL-2R, and TNF alpha (but not IL-6) were significantly higher in RA patients than in controls. Significant decreases in sIL-2R and p55 concentrations were associated with clinical improvement and were observed in patients treated with MTX, but not AZA. Both treatments induced decreases in IL-6 concentrations, but circulating AZA (or its metabolites) appears to interfere with the measurement of IL-6 bioactivity. TNF alpha and p75 levels did not show significant changes. CONCLUSION: Measurement of circulating sIL-2R, p55, and IL-6 may be useful in the evaluation of RA disease activity and response to therapy. Interference by circulating levels of drugs must be ruled out when bioassays are used to evaluate cytokine levels.

Arthritis, Rheumatoid↗
PubMed1993

Indications for the presence of circulating peroxidized low density lipoproteins in WHHL rabbits treated with antioxidants.

Low density apolipoprotein (apo) B-100 in homozygous WHHL rabbits appears heterogeneous on SDS-PAGE. At least four high molecular weight apolipoproteins were identified in contrast to the uniform apo B-100 band in the very low density lipoprotein (VLDL) fraction of WHHL-homozygotes and the apo B containing lipoproteins present in WHHL heterozygotes or New Zealand White rabbits. We studied whether these aberrations in homozygote WHHL-LDL were due to physical changes induced by lipid peroxidation. Therefore we treated WHHL rabbits for 28 days with a standard dose of 1% probucol or with a dose of 0.1% vitamin E and studied the parameters indicating lipid peroxidation in circulating LDL and in vitro in relation to its antioxidant content. The LDL of probucol-fed rabbits appeared completely resistant against oxidation in vitro with Cu2+ ions. LDL fluorescence and serum malondialdehyde concentrations, indicators of lipid peroxidized LDL, were lower than in the control WHHL rabbits. LDL of vitamin E-fed WHHL rabbits showed a twofold increased lag phase in comparison with LDL of control-fed animals; the maximal rate of oxidation was 2- to 3-fold lower while LDL fluorescence was between the values obtained in the two other groups. Malondialdehyde concentration in the vitamin E-treated group was also decreased when compared with controls. Despite these indications of increased lipid peroxidized circulating LDL in WHHL controls which could be reversed, at least partially, by the antioxidant treatments applied, these treatments were without effect on the physical structure of LDL as examined with agarose gel electrophoresis. Neither antioxidant treatment changed the typical apo B-100 pattern in WHHL-LDL.

Animals↗
PubMed1993

The effect of cholesterol reduction on the endothelial function and progression of atherosclerosis in WHHL rabbits.

In 3-month-old homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits the effect of treatment with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor pravastatin was studied for 9 months and related to the endothelial function of the coronary arteries of isolated hearts and rings of the distal abdominal aorta. Oral administration of pravastatin in doses up to 40 mg/kg per day significantly decreased plasma cholesterol by 51% in comparison to untreated WHHL rabbits. Basal coronary flow and bradykinin-induced increase in coronary flow in Langendorff hearts of the pravastatin-treated animals were significantly greater than the flow in the control animals, whereas the metacholine-induced relaxation of abdominal aortic rings was not different and attenuated in comparison to New Zealand white rabbits. The incidence of atherosclerotic lesions in four main coronary arteries and the aorta was significantly lower in the pravastatin treated animals (25.0% and 52.8% respectively) than in untreated WHHL rabbits (34.1% and 80.0% respectively). The mean percentage of narrowing in the aorta was also significantly lower in the pravastatin-treated group (12.0%) than in the controls (25.2%). Significant correlations were found between the extent of atherosclerotic lesions and the bradykinin-induced increase in coronary flow versus plasma total cholesterol levels. Thus, in this model, long term cholesterol lowering treatment with pravastatin starting at an early age retards the progression of plaque formation and preserves the endothelium-dependent relaxation of the coronary arteries.

Animals↗
PubMed1993

Oxidation resistance, oxidation rate, and extent of oxidation of human low-density lipoprotein depend on the ratio of oleic acid content to linoleic acid content: studies in vitamin E deficient subjects.

The purpose of this study was to understand better the factors providing oxidation resistance to human low-density lipoprotein (LDL). Therefore, the susceptibility to copper-induced in vitro oxidation of LDL from vitamin E deficient patients and normal healthy subjects was studied. Surprisingly, the LDL of vitamin E deficient patients appeared less susceptible to oxidation than control LDL. Both oxidation rate and extent of oxidation, measured as diene production, were reduced when compared to control LDL. The lag time, a measure of resistance to oxidation, was not different from the lag time of LDL from healthy subjects. No relation was found between vitamin E content and resistance against oxidation. LDL from vitamin E deficient patients contained lower amounts of vitamin E, less cholesteryl esters, and increased amounts of triglycerides. Furthermore, its oleic acid content was increased and its linoleic acid content decreased. Linear regression analyses revealed that the ratio of oleic acid content to linoleic acid content was strongly correlated with the lag time, and inversely correlated with oxidation rate and extent of oxidation. Thus, LDL rich in oleic acid and poor in linoleic acid was less easily oxidized. It is concluded that the susceptibility of LDL to oxidation is determined not only by its antioxidant content, but also by other compositional factors, and more specifically by the ratio of oleic acid content to linoleic acid content.

Adult↗
PubMed1993

Decreased in vitro oxidizability of low-density lipoprotein in hypercholesterolaemic patients treated with 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors.

We studied the effects of the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors simvastatin and pravastatin on the in vitro susceptibility of low-density lipoprotein (LDL) to oxidation. Twenty-three hypercholesterolaemic patients (mean serum cholesterol 9.7 mmol l-1) were treated with increasing doses of either simvastatin or pravastatin for 18 weeks. No significant differences in effect on lipid levels between the two drugs were found. Treatment resulted in lowering of total cholesterol and LDL-cholesterol by maximally 30% and 34%, respectively. Chemical composition analysis showed that LDL particles contained relatively more protein and less free cholesterol and cholesteryl-ester after treatment. The LDL cholesterol/protein ratio decreased from 1.24 +/- 0.21 to 0.97 +/- 0.23 (n = 20). By continuous monitoring of in vitro oxidation it appeared that LDL was less susceptible to oxidation after drug treatment. Maximal rate of diene production was significantly decreased from 19.7 +/- 3.1 to 18.5 +/- 3.3 nmol min-1 mg-1 LDL; total diene production decreased significantly from 420.3 +/- 67.6 to 380.5 +/- 49.1 nmol mg-1 LDL; the lag time was unchanged throughout the study. These studies show that HMG-CoA reductase inhibitors reduce the oxidizability of LDL by altering its composition.

Adult↗
PubMed1993

Identification of multiple dense LDL subfractions with enhanced susceptibility to in vitro oxidation among hypertriglyceridemic subjects. Normalization after clofibrate treatment.

The influence of different plasma triglyceride concentrations on the heterogeneity of low density lipoprotein (LDL) and on the susceptibility of LDL to copper oxidation was investigated. By density gradient ultracentrifugation, LDL subfractions were isolated from the plasma of 10 normolipidemic control subjects and 12 hypertriglyceridemic patients both before and after clofibrate treatment. In the plasma of control subjects three LDL subfractions were present: LDL1 (d = 1.030-1.033 g/mL), LDL2 (d = 1.033-1.040 g/mL), and LDL3 (d = 1.040-1.045 g/mL). In the plasma of nine moderately hypertriglyceridemic subjects up to five LDL subfractions could be detected: LDL1-LDL3, LDL4 (d = 1.045-1.049 g/mL), and LDL5 (d = 1.049-1.054 g/mL). This polydispersity of LDL was replaced by monodispersity with increasing plasma triglyceride concentrations in three subjects with chylomicronemia, in whom LDL was concentrated in the narrow LDL5 density range. Clofibrate treatment resulted in a lighter LDL subfraction pattern (LDL1-LDL4). In both the control and the moderately hypertriglyceridemic subjects, the small dense LDL subfractions appeared more prone to oxidative modification in vitro than the light LDL subfractions, as measured by the decreased lag time preceding the onset of lipid peroxidation. Furthermore, the dense LDL subfractions were more extensively modified over time, as shown by an increased oxidation rate and a greater number of dienes formed after 6 hours of oxidation. These results suggest an enhanced atherogenic potential of the small, dense LDL subfractions within each LDL subfraction profile. The hypertriglyceridemic LDL subfractions before therapy (LDL3-LDL5) were less resistant to in vitro oxidation than the light, control LDL subfractions (LDL1-LDL3).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1993

Differences in the low density lipoprotein subfraction profile between oral contraceptive users and controls.

To investigate the effect of low dose oral contraceptives on the low density lipoprotein (LDL) subfraction profile, the distribution of the LDL subfraction patterns in 20 premenopausal women on oral contraceptive (OC) therapy and 41 premenopausal women not taking gonadal hormones was studied. The LDL subfraction patterns were identified by density gradient ultracentrifugation and each individual LDL subfraction pattern was characterized by the relative contribution of three major LDL subfractions: light, LDL1; intermediate, LDL2; and dense, LDL3 to total LDL. Serum lipid and lipoprotein levels were similar in OC users and controls, except for significantly higher triglyceride levels in OC users. As for the LDL subfraction patterns, among the OC users the mean relative contribution of dense LDL3 to total LDL was significantly higher than in the controls (32% +/- 8% vs. 26% +/- 13%, P < 0.05), whereas the relative contribution of light LDL1 to total LDL was significantly lower (27% +/- 8% vs. 34% +/- 10%, P < 0.01), indicating a higher prevalence of the more dense LDL subfraction patterns among OC users. Furthermore, the distribution of the LDL subfraction patterns in OC users (27% LDL1, 41% LDL2, and 32% LDL3) resembled that of men (25% LDL1, 43% LDL2, and 33% LDL3, n = 59). Statistical analysis revealed that OC use was significantly associated with a more dense LDL subfraction pattern, characterized by an increased relative contribution of LDL3 (+6%, P < 0.05) and a decreased relative contribution of LDL1 (-6%, P < 0.01), even after correcting for the influence of lipid and lipoprotein levels, which in controls were shown to have a significant relation to LDL3 and LDL1, respectively. So, independent of the lipid and lipoprotein levels, low dose OC alter the composition of LDL to a heavy, dense LDL subfraction profile, which reportedly has been associated with an increased risk of atherosclerosis.

Cholesterol↗
PubMed1993

The effect of simvastatin treatment on the low-density lipoprotein subfraction profile and composition in familial hypercholesterolaemia.

The effect of simvastatin treatment on the low-density lipoprotein (LDL) subfraction profile was studied in 26 patients with familial hypercholesterolaemia. Before treatment LDL consisted of three LDL subfractions, using density-gradient ultracentrifugation (LDL1, LDL2 and LDL3) present in a relatively narrow density range (d = 1.030-1.045 g/ml). Simvastatin did not influence this profile with respect to the number and density range of the LDL subfractions. However, the composition of the isolated LDL subfractions changed after treatment, as evidenced by the reversal towards normal of the increased cholesterol/protein ratio (mean 1.51 before vs. 1.38 after therapy, p < 0.01; mean 1.36 in normolipidaemic subjects). When the subjects were stratified by their plasma triglyceride levels or the change in plasma triglycerides during simvastatin therapy, a strong dependence of the LDL subfraction profile and its composition on plasma triglyceride levels was observed; increasing plasma triglyceride levels were associated with a more dense LDL subfraction profile, characterized by a high relative contribution of dense LDL3 to total LDL and changes in LDL composition, reflected by a relatively low cholesterol/protein ratio. Our results indicate that in patients with familial hypercholesterolaemia: (1) plasma triglyceride levels have an important role in determining the properties of LDL and (2) simvastatin treatment results in changes in composition of LDL, which may affect the intrinsic metabolic characteristics and thus the atherogenic potential of LDL.

Adolescent↗
PubMed1993

The role of modification of lipoproteins and of the immune system in early atherogenesis.

Not only the plasma cholesterol level, but also postsecretory modifications of lipoproteins appear to be of influence in atherogenesis. Evidence that several forms of modification, especially oxidation, occur in vivo is rapidly accumulating, although their clinical relevance remains uncertain. Modification of lipoproteins has been demonstrated in persons with such well-known risk factors of premature atherosclerosis as smoking, diabetes mellitus and hyperlipidaemia. Because there is a relation between the amount of natural antioxidants in the plasma and the risk of atherosclerosis, and because exogenous antioxidants appear to retard atherosclerosis without influencing the plasma cholesterol level, antioxidants may prove to be of use in the prevention of atherosclerosis. There are strong indications for a role of the immune system in atherogenesis. Modified lipoproteins are highly immunogenic and stimulate immunocompetent cells to secrete vasoactive factors and cytokines. From animal studies it appears that pro- and antioxidative conditions can modulate these processes. It is concluded that additional research on the relation between lipoprotein modification and the immune system, and on the possible beneficial effects of antioxidants in atherogenesis is warranted, not only to elucidate further the mechanism of atherosclerosis, but also to develop new approaches to the prevention of atherosclerosis.

Animals↗
PubMed1993

Differences in LDL receptor-mediated metabolism of three low density lipoprotein subfractions by human monocyte-derived macrophages: impact on the risk for atherosclerosis.

The metabolism of three low density lipoprotein (LDL) subfractions by human monocyte-derived macrophages (HMDM) through the LDL receptor pathway was studied. The three LDL subfractions, very light LDL1, light LDL2 and heavy LDL3, were isolated from serum pools of normolipidemic subjects by density gradient ultracentrifugation. The LDL subfractions were shown to differ in molecular size and chemical composition but not in electrophoretic mobility on agarose gel. Cell specific association, cell specific degradation and stimulation of cholesteryl esterification were determined in parallel after incubation of HMDM with increasing amounts of LDL-protein of the three LDL subfractions. The experiments were repeated four times with freshly prepared LDL subfractions. Both the cell specific association and degradation increased more with increasing LDL-protein concentration for LDL1 than for LDL3 (p < 0.001). The results for LDL2 were intermediate between those for LDL1 and LDL3 and differed significantly from both (p < 0.05). For the stimulation of cholesteryl ester formation, the curves for LDL1 and LDL2 increased more with increasing LDL-protein concentration than that for LDL3 (p < 0.001); the results for LDL1 and LDL2 did not differ significantly from each other. These differences between LDL subfractions in cholesteryl esterification were independent of the cholesterol content of the LDL subfractions. The results show that LDL subfractions have different rates of LDL receptor-mediated catabolism by HMDM. As HMDM play an important role in the formation of atherosclerotic plaques, the differences between the LDL subfractions in catabolism by HMDM, may result in differences in atherogenicity between LDL subfractions isolated from normolipidemic subjects.

Analysis of Variance↗
PubMed1993

Evaluation of indium-111-polyclonal immunoglobulin G to quantitate atherosclerosis in Watanabe heritable hyperlipidemic rabbits with scintigraphy: effect of age and treatment with antioxidants or ethinylestradiol.

Scintigraphic detection of atherosclerotic lesions using 111In-polyclonal IgG was studied. In Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model for hypercholesterolemia with spontaneous atherosclerosis, aged WHHL rabbits incorporated more 111In-IgG into atherosclerotic lesions than young WHHL or control NZW rabbits. This result is in agreement with histological analysis. However, due to the low ratio of lesion-incorporated radioactivity to circulating radioactivity, in vivo gamma imaging of atherosclerosis with 111In-IgG scintigraphy was unsuccessful. Interventional agents, Probucol or vitamin E, used for 28 days to reduce the amount of autoantibodies produced against biological modified low-density lipoproteins did not produce differences in 111In-IgG incorporation into the aorta ex vivo. Ethinylestradiol, used for 28 days, exhibited similar incorporation with decreased serum cholesterol by 45%. Although atherosclerosis histology and lesion surfaces of WHHL rabbits are similar to those in adult humans, it is obvious that noninvasive gamma imaging with polyclonal 111In scintigraphy is not reliable for serial evaluation of the extent of atherosclerosis. Our results emphasize the need to develop pharmaceuticals to image atherosclerosis.

Age Factors↗
PubMed1992

Beneficial effects on serum lipoproteins by 17 beta-oestradiol-dydrogesterone therapy in postmenopausal women; a prospective study.

STUDY OBJECTIVE: To study the possible changes of reproductive hormones, sex hormone binding globulin, serum lipids and lipoproteins, lipoprotein (a) included, coagulation and glucose in postmenopausal women treated with 17 beta-oestradiol and cyclic dydrogesterone for 14 days per 28 days treatment cycle. DESIGN: Open longitudinal prospective study. DURATION: Twelve 28 days treatment cycles. SETTING: Gynaecological department of university hospital. SUBJECTS: 27 healthy postmenopausal women. RESULTS: After treatment for six cycles serum concentrations of FSH and LH decreased significantly with 43.0% and 24.4%, respectively. Serum concentrations of 17 beta-oestradiol and oestrone increased significantly with 302% and 792%, respectively, and SHBG increased as well with 111% (P < 0.01). Serum total cholesterol decreased with 9.0% (P < 0.01). Serum VLDL-cholesterol did not change significantly. Serum LDL-cholesterol decreased with 16.3% (P < 0.01) and HDL-cholesterol increased with 8.0% (P < 0.01). This was accompanied with similar significant changes in the apolipoproteins: apolipoprotein A-I rose with 14.4% and apolipoprotein B decreased with 6.0%. Serum triglycerides and VLDL-triglycerides increased significantly with 14.4% and 17.9%, respectively. Lipoprotein (a) decreased with 17.5% (P < 0.01). These results more or less sustained at cycle 12 of treatment. Serum concentrations of antithrombin III and glucose did not change. Fibrinogen decreased slightly but significantly below the initial value. CONCLUSIONS: This combination replacement therapy gives beneficial changes in lipid-metabolism, indicating a reduced risk of developing coronary heart disease without unfavourably changing coagulation and glucose metabolism. The expected beneficial changes with oestradiol alone are not counteracted by the intermittent addition of dydrogesterone. Therefore this oestrogen/progestagen scheme can, indeed, be recommended for use in HRT.

Apolipoproteins A↗