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Biomedical subjects

P D English

Publications and source records attributed to P D English.

18 recordsLinked to original sources
PubMed1985

Inhibitors of blood platelet aggregation. Effects of some 1,2-benzisothiazol-3-ones on platelet responsiveness to adenosine diphosphate and collagen.

A series of substituted 1,2-benzisothiazol-3-ones was synthesized, and the compounds were tested for ability to inhibit platelet aggregation induced by adenosine diphosphate and collagen in rats and guinea pigs ex vivo. Alkyl substituents at the 2-position bearing a basic group were necessary for ex vivo activity. Several of the compounds were potent inhibitors of adenosine diphosphate induced first-phase aggregation, but adverse toxicological findings terminated their further development. Preliminary studies suggested that inhibition of aggregation was not attributable to inhibition of prostanoid synthesis or to raised levels of cyclic 3',5'-adenosine monophosphate.

Adenosine Diphosphate↗
PubMed1984

Comparison of the hypotensive effects of streptokinase-(human) plasmin activator complex and BRL 26921 (p-anisoylated streptokinase-plasminogen activator complex) in the dog after high dose, bolus administration.

In view of current interest in the possibility of rapid, high-dose administration of thrombolytic agents by the intravenous route in patients with coronary thrombosis (AMI), a study of this technique was carried out in the dog. Streptokinase-(human) plasmin activator complex (SK-Pm) and BRL 26921 (p-anisoylated streptokinase-(human) plasminogen activator complex) were each given at equivalent doses (28,500 IU/kg and 800 micrograms/kg respectively) to groups of beagle dogs by rapid injection over 10 sec and their effects on blood pressure, plasmin formation and kallikrein production were compared over the next 3h. SK-Pm produced, within 1-3 min, a pronounced hypotensive effect that was kinetically related to a rapid and steep rise in systemic plasmin and kallikrein concentrations. BRL 26921 had no hypotensive effect, the rise in plasmin production was slower and the rate and extent of kallikrein formation was significantly less than in the SK-Pm group.

Animals↗
PubMed1984

Acyl-enzymes as thrombolytic agents in dog models of venous thrombosis and pulmonary embolism.

A quantitative model of venous thrombosis in the beagle dog is described. The model was adapted to permit ageing of isolated experimental clots in vivo. A model of acute pulmonary embolism in this species is also described. In the venous thrombosis model, infusion of streptokinase (SK) or SK-activated human plasmin gave significant lysis but bolus doses of SK. plasmin complex were ineffective. Active site anisoylated derivatives of SK. plasminogen complex, SK-activated plasmin and activator-free plasmin were all active when given as bolus doses in both models. At lytic doses, the acyl-enzymes caused fewer side-effects attributable to plasminaemia than the corresponding unmodified enzymes.

Animals↗
PubMed1982

Acyl-enzymes as thrombolytic agents in a rabbit model of venous thrombosis.

A derivative of human lys-plasmin in which the active site has been reversibly acylated (BRL 26920; p-anisoyl human lys-plasmin) has been examined as a fibrinolytic agent in a previously described rabbit model of venous thrombosis and shown to be significantly more active and less fibrinogenolytic than free plasmin. A p-anisoylated derivative of a streptokinase (SK)-activated plasmin preparation was significantly less fibrinogenolytic in vivo than the non-acylated enzyme. Acylation increased the fibrinolytic activity of preparations of SK-plasmin activator complexes. BRL 26921, the active site anisoylated derivative of the primary 2-chain SK-plasminogen complex was the most potent fibrinolytic agent studied. SK-Val442-plasminogen complexes, free or acylated, were biologically inactive in this model and confirm the essential nature of fibrin binding processes for effective thrombolysis in vivo.

Acylation↗
PubMed1981

The evaluation of plasmin and streptokinase activator complexes in a new rabbit model of venous thrombosis.

A new quantitative model for the examination of potential thrombolytic agents is described. A thrombus was formed in the inferior vena cava of the rabbit, using 125 I-labelled fibrinogen mixed with a standard amount of thromboplastin. The thrombus was anchored securely by means of a woollen thread inserted longitudinally into the lumen of the vein. Thrombotic extension of the radioactive clot and rethrombosis during the experimental period (5 h) were prevented by the administration of intravenous heparin. In control animals, the thrombus remained stable and there was no rise in te radioactivity of the circulating blood during 5 h. In animals given thrombolytic agents, lysis could be followed continuously by measuring the rise in blood radioactivity. Total lysis was determined by counting the radio-label in the residual clot after treatment. The model has been used to study the thrombolytic activity of streptokinase-human plasminogen complexes, activator-free plasmins of human and porcine origin, and human plasmin produced by streptokinase (SK) activation of human plasminogen. The role of activator complexes in the thrombolytic activity of SK-activated plasmin is discussed.

Animals↗
PubMed1981

The thrombolytic activity of streptokinase in the rabbit.

The activity of streptokinase (SK) has been examined in a rabbit model of venous thrombosis. Significant thrombolysis was observed at low doses of SK without evidence of systemic activation of the fibrinolytic system. The origin of the specificity of SK-induced fibrinolysis in the rabbit was explored, using a chromogenic substrate coupled assay to measure the enhancement of plasmin generation in the presence of rabbit fibrin. The results obtained suggest that rabbit fibrin influences the fibrinolytic system at three points, viz: the assembly of an activator complex from rabbit plasminogen and SK; the activity of that activator complex towards further rabbit plasminogen; and the activity of the resulting rabbit plasmin in the presence of plasma inhibitors.

Animals↗
PubMed1981

Fibrinolysis with acyl-enzymes: a new approach to thrombolytic therapy.

Deep vein thrombosis in man presents a considerable clinical challenge. Despite the availability of prophylactic measures, therapeutic thrombolysis is often necessary, but is difficult and hazardous. Treatments have included the administration of plasmin, other less specific proteolytic enzymes, the indirect plasminogen activator, streptokinase, and the direct activators, urokinase and streptokinase-human plasmin complex. All these treatments have been associated with some haemostatic breakdown, which has discouraged their widespread application. The enzyme components of the coagulation and fibrinolytic pathways can, in general, be classed as serine proteases, with a catalytic mechanism which operates via acyl-enzyme intermediates. Chase and Shaw showed that p-nitrophenyl-p'-guanidinobenzoate could specifically acylate the active centre of trypsin-like enzymes, giving rise to a stable p-guanidinobenzoyl enzyme and other stable acyl-enzymes have since been described. We report here the fibrinolytic use of acylated derivatives of plasmin (E.C.3.4.21.7) and streptokinase-plasmin(ogen) complexes.

Acylation↗
PubMed1972

The role of cytochrome P-450 in cholesterol biogenesis and catabolism.

1. Adjuvant-induced arthritis in rats is accompanied by a loss of activity of the drug-metabolizing enzyme system and a decrease in hepatic cytochrome P-450. 2. Arthritic rats have normal serum and liver cholesterol concentrations. 3. The rate of biogenesis of cholesterol in vivo and in vitro from either [(14)C]acetate or [(14)C]mevalonate in arthritic rats was the same as or greater than that found in control rats. 4. Treatment of rats with carbon disulphide (1ml/kg) resulted in a loss of drug-metabolizing-enzyme activity and increased cholesterol biogenesis. 5. The activity of cholesterol 7alpha-hydroxylase in adjuvant-induced arthritic rats did not differ significantly from that in control rats. 6. Rats fed with cholestyramine had an elevated hepatic cholesterol 7alpha-hydroxylase activity, but neither the concentration of cytochrome P-450 nor the activity of the drug-hydroxylating enzyme, aminopyrine demethylase, was affected. 7. The relationships between drug hydroxylation and cholesterol metabolism are discussed.

Acetates↗
PubMed1972

The identification of a lipid-mobilizing factor from sheep midbrain.

The mass spectrum of a lipolytic substance from purified sheep midbrain extract indicated that it was isoprenaline, not N-n-propylnoradrenaline, noradrenaline or adrenaline. The identification of the lipid-mobilizing factor as isoprenaline was confirmed qualitatively by t.l.c. and g.l.c. and quantitatively by determination of its lipolytic activity and u.v. absorption and by fluorimetric determination of its catecholamine content.

Adipose Tissue↗
PubMed1972

A Cell Wall-degrading Endopolygalacturonase Secreted by Colletotrichum lindemuthianum.

Cultures of Colletotrichum lindemuthianum (Saccardo and Magnus) Scribner have been induced to secrete an endopolygalacturonase (polygalacturonide glycanohydrolase EC3.2. 1.15). This enzyme has been brought to a high state of purity by ion exchange, gel filtration, and agarose affinity chromatography. The enzyme has optimal activity at pH 5, has an apparent molecular weight as determined by gel filtration of about 70,000, and prefers polygalacturonic acid to pectin as its substrate. The enzyme, while hydrolyzing only 1% of the glycosidic bonds, reduces the viscosity of a polygalacturonic solution by 50%. Nevertheless, the initial as well as the final products of polygalacturonic acid hydrolysis are predominantly tri- and digalacturonic acid and, to a lesser extent, monogalacturonic acid. The purified enzyme catalyzes the removal of about 80% of the galacturonic acid residues of cell walls isolated from suspension-cultured sycamore cells (Acer pseudoplatanus) as well as from the walls isolated from 8-day-old Red Kidney bean (Phaseolus vulgaris) hypocotyls.

Journal Article↗
PubMed1971

Host-Pathogen Interactions: II. Parameters Affecting Polysaccharide-degrading Enzyme Secretion by Colletotrichum lindemuthianum Grown in Culture.

The effect of a number of physiological variables on the secretion of polysaccharide-degrading enzymes by culture-grown Colletotrichum lindemuthianum (Saccardo and Magnus) Scribner was determined. The number of spores used to inoculate cultures grown on isolated bean hypocotyl cell walls affects the time after inoculation at which enzyme secretion occurs, but has no significant effect on the maximal amount of enzyme ultimately secreted. Cell walls isolated from bean leaves, first internodes, or hypocotyls (susceptible to C. lindemuthianum infection), when used as carbon source for C. lindemuthianum growth, stimulate the fungus to secrete more alpha-galactosidase than do cell walls isolated from roots (resistant to infection). The concentration of carbon source used for fungal growth determines the final level of enzyme activity in the culture fluid. The level of enzyme secretion is not proportional to fungal growth; rather, enzyme secretion is induced. Maximal alpha-galactosidase activity in the culture medium is found when the concentration of cell walls used as carbon source is 1% or greater. A higher concentration of cell walls is necessary for maximal alpha-arabinosidase activity. Galactose, when used as the carbon source, stimulates alpha-galactosidase secretion but, at comparable concentrations, is less effective in doing so than are cell walls. Polysaccharide-degrading enzymes are secreted by C. lindemuthianum at different times during growth of the pathogen on isolated cell walls. Pectinase and alpha-arabinosidase are secreted first, followed by beta-xylosidase and cellulase, then beta-glucosidase, and, finally, alpha-galactosidase.

Journal Article↗
PubMed1969

Host-Pathogen Interactions: I. A Correlation Between alpha-Galactosidase Production and Virulence.

Resistance or susceptibility of Red Kidney, Pinto and Small White beans (Phaseolus vulgaris) to the alpha, beta, and gamma strains of Colletotrichum lindemuthianum was either confirmed or established. These fungal strains secrete alpha-galactosidase, beta-galactosidase and beta-xylosidase when grown on cell walls isolated from the hypocotyls of any of the above bean varieties. These enzymes effectively degrade cell walls isolated from susceptible 5-day old hypocotyls but degrade only slightly the walls isolated from resistant 18-day old hypocotyls. The amounts of the beta-galactosidase and beta-xylosidase secreted by the 3 fungal strains are relatively low and are approximately equivalent. The secretion of these 2 enzymes is not dependent upon the bean variety from which the hypocotyl cell walls used as a carbon source were isolated. However, the fungal strains secrete greater amounts of alpha-galactosidase when grown on hypocotyl cell walls isolated from susceptible plants than when grown on walls from resistant plants. Virulent isolates of the fungus, when grown on hypocotyl cell walls isolated from a susceptible plant, secrete more alpha-galactosidase than do attenuated (avirulent) isolates of the same fungal strain grown under the same conditions. The alpha-galactosidase secreted by each of the fungal strains is capable of removing galactose from the hypocotyl cell walls of each bean variety tested. Galactose is removed from the cell walls of each variety at the same rate regardless of whether the cell walls were isolated from a susceptible or resistant plant.

Journal Article↗
PubMed1968

Changes in cell wall polysaccharides associated with growth.

Changes in the polysaccharide composition of Phaseolus vulgaris, P. aureus, and Zea mays cell walls were studied during the first 28 days of seedling development using a gas chromatographic method for the analysis of neutral sugars. Acid hydrolysis of cell wall material from young tissues liberates rhamnose, fucose, arabinose, xylose, mannose, galactose, and glucose which collectively can account for as much as 70% of the dry weight of the wall. Mature walls in fully expanded tissues of these same plants contain less of these constituents (10%-20% of dry wt). Gross differences are observed between developmental patterns of the cell wall in the various parts of a seedling, such as root, stem, and leaf. The general patterns of wall polysaccharide composition change, however, are similar for analogous organs among the varieties of a species. Small but significant differences in the rates of change in sugar composition were detected between varieties of the same species which exhibited different growth patterns. The cell walls of species which are further removed phylogenetically exhibit even more dissimilar developmental patterns. The results demonstrate the dynamic nature of the cell wall during growth as well as the quantitative and qualitative exactness with which the biosynthesis of plant cell walls is regulated.

Journal Article↗
PubMed1967

The specific nature of plant cell wall polysaccharides.

Polysaccharide compositions of cell walls were assessed by quantitative analyses of the component sugars. Cell walls were hydrolyzed in 2 n trifluoroacetic acid and the liberated sugars reduced to their respective alditols. The alditols were acetylated and the resulting alditol acetates separated by gas chromatography. Quantitative assay of the alditol acetates was accomplished by electronically integrating the detector output of the gas chromatograph. Myo-inositol, introduced into the sample prior to hydrolysis, served as an internal standard.The cell wall polysaccharide compositions of plant varieties within a given species are essentially identical. However, differences in the sugar composition were observed in cell walls prepared from different species of the same as well as of different genera. The fact that the wall compositions of different varieties of the same species are the same indicates that the biosynthesis of cell wall polysaccharides is genetically regulated. The cell walls of various morphological parts (roots, hypocotyls, first internodes and primary leaves) of bean plants were each found to have a characteristic sugar composition.It was found that the cell wall sugar composition of suspension-cultured sycamore cells could be altered by growing the cells on different carbon sources. This demonstrates that the biosynthesis of cell wall polysaccharides can be manipulated without fatal consequences.

Journal Article↗