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Biomedical subjects

B Angelin

Publications and source records attributed to B Angelin.

At least 145 records · Page 8Linked to original sources
PubMed1991

Hepatic cholesterol metabolism in cholesterol gallstone disease.

Hepatic cholesterol metabolism was examined in 27 Swedish patients with cholesterol gallstone disease and in 13 patients free of gallstones operated for roentgenographically suspect polyps in the gallbladder. All 40 patients underwent cholecystectomy, and a liver biopsy and gallbladder bile were obtained at surgery. The cholesterol saturation of gallbladder bile was significantly higher in patients with gallstones compared to the gallstone-free controls (131 +/- 13 vs. 75 +/- 5%, P less than 0.001). Microsomal 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity, governing cholesterol synthesis, did not differ between gallstone and gallstone-free patients (104 +/- 11 vs. and 109 +/- 22 pmol/min per mg protein, respectively). The activity of cholesterol 7 alpha-hydroxylase, catalyzing the catabolism of cholesterol to bile acids, was not significantly decreased in gallstone patients (6.2 +/- 1.1 vs. 8.0 +/- 2.0 pmol/min per mg protein). The capacity to esterify cholesterol, judged by the activity of acyl coenzyme A:cholesterol acyltransferase (ACAT), was similar in gallstone and gallstone-free patients (5.4 +/- 0.4 vs. 6.7 +/- 1.1 pmol/min per mg protein). In the presence of exogenous cholesterol, ACAT activity increased by more than fourfold in both groups. No correlation was found between the saturation of gallbladder bile and any of the mentioned enzyme activities in gallstone patients. It is concluded that distinct abnormalities in cholesterol metabolizing enzymes are not of major importance for development of gallstones in Swedish patients with cholesterol gallstone disease. The results support the contention that the etiology of cholesterol gallstones is multifactorial.

Adolescent↗
PubMed1990

Influence of pravastatin, a specific inhibitor of HMG-CoA reductase, on hepatic metabolism of cholesterol.

BACKGROUND: Inhibitors of the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, are now used frequently to treat hypercholesterolemia. We studied the effects of specific inhibition of cholesterol synthesis by one of these agents (pravastatin) on the hepatic metabolism of cholesterol in patients with gallstone disease who were scheduled to undergo cholecystectomy. METHODS: Ten patients were treated with pravastatin (20 mg twice a day) for three weeks before cholecystectomy; 20 patients not treated served as controls. A liver specimen was obtained from each patient at operation, and the activities of rate-determining enzymes in cholesterol metabolism as well as low-density-lipoprotein (LDL)-receptor binding activity were determined. RESULTS: Pravastatin therapy reduced plasma total cholesterol by 26 percent and LDL cholesterol by 39 percent (P less than 0.005). Serum levels of free lathosterol, a precursor of cholesterol whose concentration reflects the rate of cholesterol synthesis in vivo, decreased by 63 percent (P less than 0.005), indicating reduced de novo biosynthesis of cholesterol. Microsomal HMG-CoA reductase activity, when analyzed in vitro in the absence of the inhibitor, was increased 11.8-fold (1344 +/- 311 vs. 105 +/- 14 pmol per minute per milligram of protein in the controls; P less than 0.001). The expression of LDL receptors was increased by 180 percent (P less than 0.005), whereas the activities of cholesterol 7 alpha-hydroxylase (which governs bile acid synthesis) and of acyl-coenzyme A:cholesterol O-acyltransferase (which regulates cholesterol esterification) were unaffected by treatment. CONCLUSIONS: Inhibition of hepatic HMG-CoA reductase by pravastatin results in an increased expression of hepatic LDL receptors, which explains the lowered plasma levels of LDL cholesterol.

Aged↗
PubMed1990

Influence of metoprolol treatment on sympatho-adrenal activation of fibrinolysis.

The effects of mental stress (a colour word conflict test, CWT) and adrenaline infusions (0.1 and 0.4 nmol kg-1 min-1) on t-PA activity, t-PA antigen, PAI-1 activity and PAI-1 antigen were studied in 18 healthy male volunteers. Furthermore, the effects of metoprolol (200 mg/day during 1 week) or placebo (double-blind cross-over study) on fibrinolytic responses to sympatho-adrenal activation, and relationships between fibrinolysis and blood lipids were investigated. Low and high dose adrenaline infusions yielding plasma adrenaline levels of 0.9 +/- 0.1 and 3.4 +/- 0.4 nmol/l, respectively, dose-dependently increased t-PA levels with a concomitant decrease in PAI-1 levels. A similar, but weaker, fibrinolytic response seemed to occur during CWT, when plasma adrenaline levels were only moderately increased (to 0.4 +/- 0.1 nmol/l). Metoprolol treatment did not influence the resting levels of the fibrinolytic variables studied, but tended to enhance the t-PA response to CWT and further reduce PAI-1 during adrenaline infusion. Metoprolol treatment was not accompanied by any rise in PAI-1 levels despite drug induced elevations of triglyceride levels. Thus, the present study shows that sympatho-adrenal activation increases fibrinolytic activity in vivo and that metoprolol treatment may have a favourable influence on this activity.

Adrenal Glands↗
PubMed1990

Apolipoprotein(a) and ischaemic heart disease in familial hypercholesterolaemia.

Serum concentrations of apolipoprotein(a) were measured in patients with heterozygous familial hypercholesterolaemia. The levels in 47 patients were a median of 2.5 times higher than those in controls matched for age and sex (240 [range 25-1245] vs 97 [7-1040] mg/l). Among patients with familial hypercholesterolaemia apo(a) levels were higher in those with (n = 48) than in those without (n = 72) ischaemic heart disease (283 [18-1245] vs 144 [7-741] mg/l); both in univariate and multivariate analysis serum apo(a) was the most significant variable distinguishing between the groups. Despite reducing LDL cholesterol by 30%, treatment with cholestyramine or pravastatin did not reduce apo(a) levels in these patients. These findings support the concept that apo(a) concentration is a genetic trait predisposing to ischaemic heart disease and imply that it may be useful in the identification of familial hypercholesterolaemia patients at high risk of coronary disease.

Adult↗
PubMed1990

Low density lipoprotein receptor activity in human intracranial tumors and its relation to the cholesterol requirement.

The receptor binding of low density lipoprotein (LDL) was determined in homogenates of surgically removed specimens from primary and metastatic intracranial tumors and in some cases also from surrounding brain. Seventy-one specimens from 63 patients were analyzed. In a subsample of 16 specimens from 13 patients, the activity of 3-hydroxy-3-methylglutaryl-CoA reductase was assayed in parallel. The LDL binding in the tumors varied over a wide range. A significantly higher LDL binding activity was found when all tumor samples were compared to brain (P less than 0.05). In the three patients where LDL receptor and 3-hydroxy-3-methylglutaryl-CoA reductase activities were assayed in both tumor tissue and surrounding brain, it was found that the receptor or the enzyme activity was increased in the tumors. It is suggested that certain intracranial tumors have an increased cholesterol requirement and that this may be fulfilled by an enhanced LDL receptor activity or an increased 3-hydroxy-3-methylglutaryl-CoA reductase activity. The data indicate that the LDL receptor activity may be regulated independently of the reductase in intracranial tumors.

Brain Neoplasms↗
PubMed1990

Characteristics of biliary lipid metabolism after liver transplantation.

Biliary lipid metabolism was studied after 10 liver transplantations with continuous drainage of bile. Within 3 wk after transplantation, the new liver produced bile with concentrations of biliary lipids in agreement with those reported for T-tube bile in cholecystectolized nontransplanted subjects. Although changes in biliary lipid composition occurred swiftly in response to various forms of disturbed liver function, they did not provide substantially more information than did standard serum tests or simple measurements of bile flow in most patients. Secretion rates of phospholipids and cholesterol were found to be completely bile acid dependent. For each micromole of bile acids, 0.22 and 0.08 mumol of phospholipids and cholesterol were secreted, respectively. When bile flow was related to bile acid output, a linear relationship was found (r = 0.89), with a positive intercept indicating a bile acid-independent bile flow of approximately 44 microliters/min. Analysis of individual bile acids showed almost exclusively primary bile acids. The relative proportion of chenodeoxycholic acid was more prominent during the first days after transplantation. Different explanations for this are discussed.

Adult↗
PubMed1990

Relative absorption of the two enantiomers of terbutaline after duodenal administration.

The absorption of the two enantiomers of terbutaline, (+)-terbutaline and (-)-terbutaline, and of the racemate, (+/-)-terbutaline, has been studied in six healthy volunteers using a newly developed intestinal perfusion technique. The area under the plasma concentration curve for the (-)-enantiomer was more than twice that for the (+)-enantiomer. The data demonstrate a clear difference in absorption efficiency between (-)- and (+)-terbutaline, but further studies are required to establish whether (-)-terbutaline influences the absorption of (+)-terbutaline.

Adult↗
PubMed1990

Interactions in the renal and biliary elimination of digoxin: stereoselective difference between quinine and quinidine.

The interactions between digoxin and quinine and quinidine that affect the renal and biliary clearances of digoxin were investigated in eight healthy subjects. Digoxin (0.5 to 0.75 mg/day) was given alone and with concomitant administration of quinine (750 mg/day) to reach a steady-state level. In four of the subjects, the study was repeated by administration of equimolar doses of the diastereoisomer quinidine together with digoxin, enabling a within-subject comparison of the effects of the two isomers on digoxin clearance. The biliary excretion of digoxin was studied by use of a modified duodenal marker perfusion technique. A marked reduction was found in the steady-state biliary clearance of digoxin from control value 134 +/- 57 ml/min (mean +/- SD) to 87 +/- 39 ml/min during treatment with quinine (p less than 0.05) and from 95 +/- 24 to 55 +/- 27 ml/min during treatment with quinidine (p less than 0.01; n = 4). Quinidine reduced the renal clearance of digoxin (155 +/- 26 versus 110 +/- 21 ml/min) (p less than 0.05; n = 4), whereas quinine had no such effect (177 +/- 40 versus 185 +/- 53 ml/min; not significant). These findings explain the difference in magnitude between quinidine and quinine in regard to the interaction with digoxin and imply a different degree of stereoselectivity for these isomers in the renal and biliary secretory systems of digoxin.

Adult↗
PubMed1990

Uptake of low density lipoproteins by human leukemic cells in vivo: relation to plasma lipoprotein levels and possible relevance for selective chemotherapy.

The success of cancer chemotherapy is dependent on the possibility to utilize biological differences between malignant and normal cells to selectively destroy the tumor cells. One such difference may be that of receptor-mediated cellular uptake of low density lipoproteins (LDLs). Previous studies have shown that leukemic cells from patients with acute myelogenous leukemia have elevated receptor-mediated uptake and degradation rates of plasma LDL in vitro compared to normal white blood and bone marrow cells, and that plasma cholesterol levels at diagnosis are inversely correlated with the LDL receptor activity of the malignant cells. An important question is whether the uptake of LDL by the leukemic cells is also increased in vivo. To evaluate the in vivo uptake of LDL, 11 adult patients with newly diagnosed acute myelogenous leukemia received an i.v. injection of [14C]-sucrose-labeled LDL. On degradation of [14C]sucrose-LDL, the radiolabeled sucrose moiety is known to remain trapped in the lysosomal compartment of the cells. After injection, radioactivity accumulated progressively for at least 12 hr in the leukemic cells. The uptake of radioactivity in vivo correlated with the rate of receptor-mediated degradation of 125I-labeled LDL by the leukemic cells assayed in vitro (r = +0.88, P less than 0.001). An inverse correlation between plasma LDL cholesterol concentrations and the in vivo cellular uptake of [14C]sucrose-LDL in whole blood (r = -0.76, P less than 0.01) indicates that the hypocholesterolemia is due to elevated LDL uptake by the leukemic cells. Postmortem biopsies from virtually all tissues were obtained from one patient, and the distribution of radioactivity revealed that the liver and bone marrow had accumulated most radioactivity; the adrenals had the highest uptake of label per gram of tissue weight. The results indicate that LDL may be used as a carrier targeting lipophilic cytotoxic drugs to leukemic cells.

Adult↗
PubMed1990

Low density lipoprotein receptor-binding activity in human tissues: quantitative importance of hepatic receptors and evidence for regulation of their expression in vivo.

The heparin-sensitive binding of 125I-labeled low-density lipoprotein (LDL) to homogenates from 18 different normal human tissues and some solid tumors was determined. The binding to adrenal and liver homogenates fulfilled criteria established for the binding of LDL to its receptor--namely, (i) saturability, (ii) sensitivity to proteolytic destruction, (iii) inhibition by EDTA, and (iv) heat sensitivity. When the binding of 125I-labeled LDL was assayed at a constant concentration (50 micrograms/ml), the adrenal gland and the ovary had the highest binding of normal tissues. The highest binding per g of tissue overall was obtained in homogenates of a gastric carcinoma and a parotid adenoma. When the weights of the parenchymatous organs were considered, the major amount of LDL receptors was contained in the liver. To study the possible regulation of hepatic LDL-receptor expression, 11 patients were pretreated with cholestyramine (8 g twice a day for 3 weeks). Increased binding activity (+105%, P less than 0.001) was obtained in homogenates from liver biopsies from the cholestyramine-treated patients as compared with 12 untreated controls. It is concluded that the liver is the most important organ for LDL catabolism in humans and that the receptor activity in this organ can be regulated upon pharmacologic intervention. Further studies are needed to confirm the possibility that certain solid tumors can exhibit high numbers of LDL receptors.

Adrenal Cortex↗
PubMed1990

Biliary lipids in familial combined hyperlipidaemia: effects of acipimox therapy.

Biliary lipid composition and plasma lipoprotein levels were determined in nine gallstone-free male patients with familial combined hyperlipidaemia (FCHL). In the basal situation, stimulated fasting duodenal bile from the patients contained a higher relative concentration of cholesterol than bile obtained from age- and sex-matched normal controls (n = 22), 6.5 +/- 0.3 (SEM) vs. 4.7 +/- 0.2 mol % (P less than 0.01). This resulted in a higher cholesterol saturation of bile from FCHL patients, 85 +/- 6 vs. 70 +/- 2% (P less than 0.05). After 6 weeks of treatment with acipimox, 750 mg day-1, total plasma triglycerides were lowered from 7.5 +/- 1.5 to 4.6 +/- 0.7 mmol l-1 (P less than 0.05) and plasma cholesterol decreased from 8.0 +/- 0.1 to 7.1 +/- 0.3 mmol l-1 (P less than 0.05) in the FCHL patients. These changes were mainly due to a decrease in very low density lipoprotein concentrations while low density lipoprotein levels remained unaltered. The relative proportion of cholesterol in stimulated fasting duodenal bile was reduced from 6.5 +/- 0.3 to 4.3 +/- 0.5 mol % (P less than 0.01), resulting in 'normalization' of biliary cholesterol saturation, from 85 +/- 6 to 58 +/- 6% (P less than 0.005). No correlations between the changes in biliary lipid composition and those in plasma lipoprotein levels were observed. The results indicate that treatment with acipimox in patients with FCHL, a disorder commonly associated with supersaturated bile, does not increase biliary cholesterol, and presumably not the risk for gallstone formation.

Adult↗
PubMed1990

Platelet aggregability in humans: contrasting in vivo and in vitro findings during sympatho-adrenal activation and relationship to serum lipids.

Platelet aggregability was studied in 18 healthy volunteers during mental stress (a colour word test; CWT) and low- and high-dose adrenaline infusions using an ex vivo technique (filtragometry) and conventional in vitro aggregometry. CWT and high-dose adrenaline (3.4 nmol l-1 in plasma) shortened filtragometry readings, suggesting increased platelet aggregability in vivo. Low-dose adrenaline had no effect despite higher adrenaline levels in plasma (0.9 nmol l-1) than during CWT (0.4 nmol l-1). Platelet sensitivity to ADP in vitro was reduced following CWT and further reduced following adrenaline infusions. In vitro, adrenaline (50 nmol l-1) had little effect on platelet aggregation per se, but enhanced aggregability evoked by ADP (at ED50). Adrenaline potentiation of ADP-induced aggregation was enhanced after CWT, but was not related to filtragometry responsiveness to stress in vivo. Serum LDL-cholesterol levels were inversely correlated to filtragometry readings at rest, suggesting an adverse influence on platelet aggregability in vivo. HDL-cholesterol levels were inversely correlated to platelet sensitivity to ADP in vitro, suggesting a positive influence. Thus, sympatho-adrenal activation enhances platelet aggregability in vivo (as assessed by ex vivo filtragometry), but adrenaline alone cannot explain the pro-aggregatory effect of mental stress. Serum lipoprotein alterations associated with increased risk for atherosclerosis seem to enhance platelet aggregability. The conventional in vitro technique may poorly reflect platelet aggregability in vivo.

Adult↗
PubMed1990

Bile acid metabolism in familial dysbetalipoproteinaemia: studies in subjects with the apolipoprotein E-2/2 phenotype.

Bile acid kinetics and biliary lipid composition were determined in seven subjects with primary dysbetalipoproteinaemia. They were all homozygous for the apolipoprotein E isoform E-2 and six of them were hyperlipidaemic (type III hyperlipoproteinaemia). With or without hyperlipidaemia, the apo E-2/2 phenotype was associated with increased bile acid formation (mean increase compared with 32 normolipidaemic controls, 43%; P less than 0.025). The biliary lipid composition was not different from that seen in the controls. The results indicate that the uptake by the liver of apo E-containing remnant particles is of importance for the regulation of hepatic cholesterol metabolism in man. It is suggested that hepatic cholesterol synthesis is stimulated in dysbetalipoproteinaemia, and that this leads to a compensatory increase in bile acid synthesis.

Adult↗
PubMed1990

Increased turnover of very low density lipoprotein triglyceride during treatment with cholestyramine in familial hypercholesterolaemia.

Kinetics of very low density lipoprotein (VLDL) triglyceride were determined in seven patients with heterozygous familial hypercholesterolaemia, using a 3H-glycerol technique. The study was repeated after 5-7 weeks of therapy with the bile acid-binding resin, cholestyramine. The rate of synthesis of VLDL triglyceride was increased by 85% (P less than 0.05) during resin therapy. Simultaneously, the fractional catabolic rate of VLDL was increased by 40% (P less than 0.02), so that only a moderate increase in plasma concentration was observed. Repeated measurements of VLDL size by electron microscopy (before, 1 week, and 5-7 weeks after initiation of therapy) indicated that a transient increase in VLDL size occurred in response to cholestyramine. The results are consistent with a stimulatory effect of bile acid sequestrants on VLDL triglyceride production and indicate that, in most subjects, a compensatory increase in VLDL triglyceride removal occurs.

Adult↗
PubMed1990

Treatment of familial hypercholesterolaemia: a controlled trial of the effects of pravastatin or cholestyramine therapy on lipoprotein and apolipoprotein levels.

The efficacy and safety of a new, selective inhibitor of cholesterol synthesis, pravastatin, and the bile acid-binding resin, cholestyramine, were compared in a randomized, double-blind study of 120 patients with familial hypercholesterolaemia. After a run-in period of 8-10 weeks with assessment of dietary habits, the patients were treated with pravastatin + placebo, placebo + cholestyramine, or placebo alone. Active pravastatin therapy was initiated with 10 mg b.i.d. for 6 weeks, and was increased to 20 mg b.i.d. for the following 6 weeks. Cholestyramine was given at 24 g d-1, or the highest tolerable dose. After 6 weeks of therapy, serum total and LDL cholesterol levels were reduced by 17% and 21%, respectively, on pravastatin treatment, whereas the corresponding reductions with cholestyramine treatment were 24% and 30%, respectively. With an increased dose of pravastatin, serum and LDL cholesterol concentrations were reduced by 23% and 28%, respectively, after 12 weeks; the effect of cholestyramine was unchanged. HDL cholesterol levels increased in response to pravastatin, by 7% and 9% after 6 and 12 weeks, respectively. Concomitant changes in the concentrations of apolipoproteins B and AI were observed. Three patients discontinued the study because of side-effects: two subjects were treated with pravastatin and one was given placebo. The prevalence of side-effects (including laboratory abnormalities) was 35% for pravastatin, 30% for placebo, and 53% (significantly higher) for cholestyramine. We conclude that pravastatin, in a 40 mg daily dose, is as effective as cholestyramine in lowering LDL cholesterol in familial hypercholesterolaemia. Since the frequency of side-effects is higher with cholestyramine, pravastatin offers a promising alternative for the therapy of this genetic disease.

Adult↗
PubMed1990

Studies with the haeme oxygenase inhibitor Sn-protoporphyrin in patients with primary biliary cirrhosis and idiopathic haemochromatosis.

Sn(tin4+)-protoporphyrin, a potent competitive inhibitor of haeme oxygenase, the rate limiting enzyme in the degradation of haeme to bile pigments, was given intravenously to six patients with primary biliary cirrhosis and to four patients with idiopathic haemochromatosis. Serum bilirubin concentrations decreased in all patients after administration of 1-2 mumol/kg body weight of the metalloporphyrin, given in two doses eight to 24 hours apart. This reduction lasted approximately four to five days after injection of the compound. Excretion of endogenous haeme in bile increased (mean increase approximately two to threefold) in parallel with the decrease in serum bilirubin concentrations in both patient groups, and the highest biliary haeme concentrations were found during the first 48 hours after treatment. Sn-protoporphyrin was cleared rapidly from plasma with a half-life of 3.4 hours. Biliary bilirubin concentrations decreased (mean decrease, 49%) in the haemochromatosis patients after Sn-protoporphyrin administration. No decrease in biliary bilirubin concentrations could be detected in the primary biliary cirrhosis patients under the same conditions. Thus, Sn-protoporphyrin treatment resulted in a decrease in serum bilirubin concentrations and an increase in biliary haeme excretion in patients with haemochromatosis and primary biliary cirrhosis, as has previously been shown in normal subjects. The results indicate that the synthetic haeme analogue inhibits haeme oxidation activity in the two patient groups studied, as it does in normal people and in experimental animals. The lack of effect of Sn-protoporphyrin on biliary bilirubin excretion in primary biliary cirrhosis may be related to a differently affected hepatic clearance system or to a different distribution of tissue bilirubin pools in this condition.

Adult↗
PubMed1990

Regulation of hepatic cholesterol metabolism in humans: stimulatory effects of cholestyramine on HMG-CoA reductase activity and low density lipoprotein receptor expression in gallstone patients.

To characterize the metabolic regulatory response to interruption of the enterohepatic circulation of bile acids, we examined the effects of cholestyramine treatment on the rate-limiting steps in cholesterol biosynthesis (HMG-CoA reductase) and bile acid production (cholesterol 7 alpha-hydroxylase) as well as on the heparin-sensitive binding of low density lipoproteins (LDL) (reflecting LDL receptor expression) in human liver. Altogether, 18 normolipidemic patients with uncomplicated cholesterol gallstone disease were treated with cholestyramine (8 g b.i.d.) for 2-3 weeks prior to cholecystectomy, and another 34 cholesterol gallstone patients served as untreated controls. Cholestyramine treatment stimulated cholesterol 7 alpha-hydroxylase more than sixfold, and increased both HMG-CoA reductase activity (552 +/- 60 pmol/min per mg protein vs 103 +/- 9 pmol/min per mg protein) and LDL receptor expression (6.1 +/- 0.8 ng/mg protein; n = 6 vs 2.2 +/- 0.3 ng/mg protein; n = 7). Moreover, there was a good correlation between HMG-CoA reductase activity and LDL receptor binding (rs = +0.71; n = 13), suggesting a simultaneous stimulatory effect to compensate for the increased hepatic cholesterol catabolism due to bile acid depletion caused by cholestyramine. Further evidence for this assumption was the finding of a significant relationship between cholesterol 7 alpha-hydroxylase activity and both LDL receptor expression (rs = +0.77; n = 13) and HMG-CoA reductase activity (rs = +0.76; n = 46). We conclude that in human liver a parallel stimulation of cholesterol synthesis and LDL receptor expression occurs in response to stimulation of bile acid synthesis.

Adult↗