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Biomedical subjects

R Fears

Publications and source records attributed to R Fears.

At least 55 records · Page 3Linked to original sources
PubMed1986

Clinical effects and kinetic properties of intravenous APSAC--anisoylated plasminogen-streptokinase activator complex (BRL 26921) in acute myocardial infarction.

Fifty patients with a first myocardial infarction presenting within 4 hours of the onset of symptoms were treated with intravenous anisoylated plasminogen-streptokinase activator complex (APSAC-BRL 26921). Vessel patency with good flow was documented in 88%. The left ventricular ejection fraction declined with the duration of symptoms before treatment (r = -0.53, P less than 0.001). The correlation persisted for the group with anterior infarction (r = -0.46, P less than 0.05) where the mean left ventricular ejection fraction prior to discharge from hospital was 36 +/- 9% compared to 49 +/- 7% for the group with inferior infarction. Reinfarction developed in 12% and mortality at 6 months for the whole group was 6%. A degree of systemic fibrinolysis did occur with a fall in mean plasma fibrinogen from 3.20 g/l to 1.08 g/l. A pharmacokinetic study was performed in six patients demonstrating a clearance half-life of fibrinolytic activity of 87.5 +/- 5.0 min. APSAC is an effective intravenous thrombolytic agent with a relatively long half-life of fibrinolytic activity.

Adult↗
PubMed1985

Interactions of insulin, glucagon and dexamethasone in controlling the activity of glycerol phosphate acyltransferase and the activity and subcellular distribution of phosphatidate phosphohydrolase in cultured rat hepatocytes.

Rat hepatocytes were incubated in monolayer culture for 8 h. Glucagon (10nM) increased the total phosphatidate phosphohydrolase activity by 1.7-fold. This effect was abolished by adding cycloheximide, actinomycin D or 500 pM-insulin to the incubations. The glucagon-induced increase was synergistic with that produced by an optimum concentration of 100 nM-dexamethasone. Theophylline (1mM) potentiated the effect of glucagon, but it did not affect the dexamethasone-induced increase in the phosphohydrolase activity. The relative proportion of the phosphohydrolase activity associated with membranes was decreased by glucagon when 0.15 mM-oleate was added 15 min before the end of the incubations to translocate the phosphohydrolase from the cytosol. This glucagon effect was not seen at 0.5 mM-oleate. Since glucagon also increased the total phosphohydrolase activity, the membrane-associated activity was maintained at 0.15 mM-oleate and was increased at 0.5 mM-oleate. This activity at both oleate concentrations was also increased in incubations that contained dexamethasone, particularly in the presence of glucagon. Insulin increased the relative proportion of phosphatidate phosphohydrolase that was associated with membranes at 0.15 mM-oleate, but not at 0.5 mM-oleate. It also decreased the absolute phosphohydrolase activity on the membranes at both oleate concentrations in incubations that also contained glucagon and dexamethasone. None of the hormonal combinations significantly altered the total glycerol phosphate acyltransferase activity. However, glucagon significantly increased the microsomal activities, and insulin had the opposite effect. Glucagon also decreased the mitochondrial acyltransferase activity. There was a highly significant correlation between the total phosphatidate phosphohydrolase activity and the synthesis of neutral lipids from glycerol phosphate and 0.5 mM-oleate in homogenates of cells from all of the hormonal combinations. Phosphatidate phosphohydrolase activity is increased in the long term by glucocorticoids and also by glucagon through cyclic AMP. In the short term, glucagon increases the concentration of fatty acid required to translocate the cytosolic reservoir of activity to the membranes on which phosphatidate is synthesized. Insulin opposes the combined actions of glucagon and glucocorticoids. The long-term events explain the large increases in the phosphohydrolase activity that occur in vivo in a variety of stress conditions. The expression of this activity depends on increases in the net availability of fatty acids and their CoA esters in the liver.

Acyltransferases↗
PubMed1985

Kinetic studies on the interaction of streptokinase and other plasminogen activators with plasminogen and fibrin.

The activation of Lys-plasminogen to plasmin by streptokinase was promoted by soluble fibrin such that Km was decreased and Vmax. increased. Enhancement was also observed when Glu-plasminogen was the substrate and was shared by the preformed streptokinase-plasminogen activator complex, indicating that the stimulation was not exerted primarily on the rate of active site formation.

Binding Sites↗
PubMed1985

Induction of a sustained fibrinolytic response by BRL 26921 in vitro.

The role of thrombus-binding in the fibrinolytic response to the acylated streptokinase.plasminogen activator complex, BRL 26921, has been examined using human plasma clots, radiolabelled with 125I-fibrin, in vitro. When clots were briefly exposed to BRL 26921, washed and returned to homologous plasma, lysis continued for up to 3 hours and attained approximately 25% of that lysis achieved by incubating with BRL 26921 for 5 hours. This continuing lysis was potentiated by return of exposed clots to alpha 2-antiplasmin-depleted plasma, or buffer and is attributed to an initial uptake of BRL 26921 rather than the binding of exogenous plasmin that was observed for streptokinase and high concentrations of urokinase. The sustained lysis is not explained by transfer of loosely-associated surface material or by dissociation of agent from the clot with reuptake from a dilute systemic pool. The response can be attributed, at least in part, to specific fibrin binding, mediated by kringles 1-4, for a low-molecular weight plasminogen (Val442) variant was less active.

Anistreplase↗
PubMed1985

Effects of cyclic AMP, glucocorticoids and insulin on the activities of phosphatidate phosphohydrolase, tyrosine aminotransferase and glycerol kinase in isolated rat hepatocytes in relation to the control of triacylglycerol synthesis and gluconeogenesis.

Rat hepatocytes were incubated in monolayer culture in modified Leibovitz L-15 medium containing either 10% (v/v) newborn-calf serum or 0.2% (w/v) fatty-acid-poor bovine serum albumin. The addition of 100 nM-dexamethasone increased the activities of both phosphatidate phosphohydrolase and tyrosine aminotransferase by about 3.5-fold after 8h, and these activities continued to rise until at least 24h. Incubating the hepatocytes in the albumin-containing medium with 10 microM- or 100 microM-8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate increased the activities of the phosphohydrolase and aminotransferase by 2.6- and 3.4-fold respectively after 8h. These increases were blocked by actinomycin D. The increases in the activities that were produced by the cyclic AMP analogue and dexamethasone were independent and approximately additive. Insulin when added alone did not alter the phosphohydrolase activity, but it increased the aminotransferase activity by 34%. The dexamethasone-induced increase in the phosphohydrolase activity was completely blocked by 7-144 microM-insulin, whereas that of the aminotransferase was only partly suppressed. Insulin had no significant Effects on the increases in the activities of phosphatidate phosphohydrolase and tyrosine aminotransferase that were produced by the cyclic AMP analogue, but this may be because the analogue is fairly resistant to degradation by the phosphodiesterase. The activity of glycerol kinase was not significantly changed by incubating the hepatocytes with insulin, dexamethasone and the cyclic AMP analogue alone or in combinations. It is proposed that high concentrations of cyclic AMP and glucocorticoids increase the total activity of phosphatidate phosphohydrolase in the liver and provide it with an increased capacity for synthesizing triacylglycerols and very-low-density lipoproteins, which is expressed when the availability of fatty acids is high. There appears to be a co-ordinated hormonal control of triacyglycerol synthesis and gluconeogenesis in diabetes and in metabolic stress to enable the liver to supply other organs with energy.

Animals↗
PubMed1984

Hyperalphalipoproteinaemic activity of BRL 26314--I. Enhanced cholesterol turnover in rats.

Administration of BRL 26314 [N-(4-chlorobenzyl)-L-phenylalanine] raises circulating high-density lipoprotein (HDL) cholesterol and lowers total triglyceride levels in rats whether maintained on stock or semi-synthetic diets. HDL is also elevated by BRL 26314 in hypothyroid rats and in rats with pre-existing hyperlipidaemia where aortic total cholesterol concentration is decreased. BRL 26314 promotes the excretion of a dose of radiolabelled cholesterol as faecal sterols and bile acids, and decreases the extent of cholesterol-radiolabelling in tissue pools, particularly the aorta and adipose tissue. The increase in cholesterol and bile acid (cholic acid) turnover distinguishes BRL 26314 from a cholestatic agent such as 1-naphthyl isothiocyanate where a superficially similar change in HDL concentration disguises an impaired cholesterol transport. BRL 26314 is not a general protein inducer but part of the mechanism of action may involve enhancement of white adipose tissue lipoprotein lipase activity.

1-Naphthylisothiocyanate↗
PubMed1984

Hyperalphalipoproteinaemic activity of BRL 26314--II. Inhibition of atherosclerosis in rabbits.

Optimization of a combination of balloon catheter-induced aortic de-endothelialization with provision of a palatable atherogenic diet to rabbits leads to hyperbetalipoproteinaemia and atherosclerosis rather than to the cholesterol-storage disease which characterized earlier models. Administration of BRL 26314 [N-(4-chlorobenzyl)-L-phenylalanine] during the induction of atherosclerosis specifically raised high-density lipoprotein (HDL) and decreased the arterial content of cholesterol and collagen in association with reduction in severity of thoracic sudanophilic lesions and intimal-thickening. This anti-atherosclerotic activity was superior to that observed for various standard compounds, and the present studies, using BRL 26314 as a pharmacological tool, provide evidence in vivo for an association between the elevation of HDL and reduction of arterial disease.

Animals↗
PubMed1982

The role of cholesterol 7 alpha-hydroxylase in the hypobetalipoproteinaemic activity of SKF-525A in rats.

Administration of SKF-525A to rats fed on a stock diet specifically decreased the serum concentration of low-density lipoprotein. SKF-525A and cholestryamine also reversed the rise in circulating concentration of both very-low density and low-density lipoprotein that was observed in rats given a sucrose-based, cholesterol-supplemented diet. The enhancement of hepatic cholesterol 7 alpha-hydroxylase by SKF-525A or by cholestyramine is accompanied by homeostatic responses by the liver which include induction of low-density lipoprotein clearance and increased cholesterogenesis to attempt to replenish sterol pools. These compensatory mechanisms are separately controlled.

Animals↗
PubMed1982

Changes in metabolism of rat kidney and liver caused by experimental diabetes and by dietary sucrose.

Two groups of rats were fed diets in which the carbohydrate components was either starch or sucrose. A third group was fed on a stock diet. Half of the animals in each group were made diabetic by injection of either streptozotocin, in two of the groups, or alloxan, in the third group. Both diabetes and sucrose-feeding increased renal gluconeogenesis as indicated by increased activities of fructose-1,6-diphosphatase and glucose-6-phosphatase. Sucrose-feeding increased fatty acid synthesis both in the liver and kidney. However, the effect of diabetes on fatty acid synthesis was different at the two tissue sites. Diabetes, whether induced by streptozotocin or alloxan, decreased fatty acid synthesis in the liver but increased the rate in the kidney. The latter response was obtained for each diet but was additive with the effect of sucrose. We conclude that the effect of diabetes on renal lipid metabolism may reflect, in part, the accelerated glucose flux. The response to both diabetes and sucrose-feeding is also possibly associated with the increased lipid required for the membrane synthesis reported previously.

Animals↗
PubMed1982

Xenobiotic cholesteryl ester formation.

1. When the novel hypolipidaemic compound 1-(4-carboxyphenoxy)-10-(4-chlorophenoxy) decane (CCD) was administered orally (250 mg/kg body weight for seven days) to rats, a lipophilic cholesterol-containing metabolite accumulated in the liver. 2. Analysis by n.m.r. spectroscopy and mass spectrometry identified the metabolite as the cholesterol conjugate of CCD. This structure was confirmed by comparison with reference material synthesized in our laboratories. 3. The xenobiotic cholesteryl ester was not further metabolized and, unlike the natural counterparts, was not transported by lipoproteins. 4. When added in vitro, the xenobiotic cholesteryl ester appeared to enhance the activity of hepatic lysosomal cholesteryl ester hydrolase and thus may contribute to the hypocholesterolaemic activity of CCD.

Animals↗
PubMed1981

Effects of chronic modification of dietary fat and carbohydrate in rats.

1. Rats were fed on diets enriched with starch, sucrose, corn oil or beef tallow for 3 weeks and the activities of various enzymes in the liver were measured. 2. The mitochondrial glycerol phosphate acyltransferase activity was lower in rats fed on the starch diet than on the two high-fat diets. 3. The non-microsomal (presumably peroxisomal) dihydroxyacetone phosphate acyltransferase activity was higher in rats fed on the starch diet and corn-oil diets than in those fed on the sucrose and beef-tallow diets. Urate oxidase activity was higher in rats fed on the starch diet than in the three other groups. There were no significant differences in the activity of acyl-CoA oxidase among the groups. 4. The activity of soluble phosphatidate phosphohydrolase was not significantly different among the dietary groups. There were increases of 3.3--4.3-fold in this activity in the dietary groups 6h after injection of corticotropin. The equivalent increases for the mitochondrial glycerol phosphate acyltransferase were 1.4--1.6 fold. 5. The corticosterone responses to the corticotropin injection were not significantly different between dietary groups. However, the corticosterone response of the rats fed on the two high-fat diets was prolonged when the rats were given an acute load of fructose [Brindley, Cooling, Glenny, Burditt & McKechnie (1981) Biochem. J. 200. 275--283]. 6. Rats fed on the high-fat diets had higher concentrations of circulating cholesterol than those fed on the starch and sucrose diets. Serum triacylglycerol concentrations were lower in the rats fed on the starch diet than in the three other groups. 7. The results are discussed in terms of the relationship between diet, hormonal balance and hepatic glycerolipid metabolism.

Adrenocorticotropic Hormone↗
PubMed1980

The effect of compactin, a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme-A reductase activity, on cholesterogenesis and serum cholesterol levels in rats and chicks.

Compactin, [7-(1,2,6,7,8,8a-hexahydro-2-methyl-8-(2-methylbutyrylox)naphthyl)-3-hydroxyheptan-5-olide], a potent competitive inhibitor of the rate-determining step in cholesterol biosynthesis, was used to study the influence of changes in cholesterogenesis on serum cholesterol levels. Up to 3 h after a single oral dose (20 or 50 mg/kg) or after the last of a series of daily oral doses (50 mg/kg for 7 or 28 days) to young, male normolipidaemic rats, compactin consistently inhibited cholesterogenesis measured using 3H20 in liver, ileum and other extrahepatic tissues without affecting fatty acid synthesis. Compactin did not reduce serum or tissue cholesterol nor affect the serum concentration of other lipids nor the ratio between lipoprotein classes. A diurnal variation in the effect of compactin on cholesterogenesis was observed. For example, by 12--20 h after dosing, cholesterogenesis at all sites was increased above the comparable control value, indicating the induction of enzyme synthesis and overall there was little effect on the mass of cholesterol synthesized per day. Similar results were obtained using male chicks. Inhibition of cholesterogenesis by compactin was also observed in cholestyramine-treated rats, in which cholesterol turnover was markedly increased, and even in cholesterol-fed rats, in which cholesterogenesis already was repressed. In neither case, however, was inhibition of cholesterogenesis accompanied by a hypocholesterolaemic effect. It is concluded that a more persistent suppression of cholesterogenesis, than that observed with compactin in the rat, may be required in order to affect serum cholesterol concentrations.

Animals↗