Search PubMed⌕ Search

Biomedical subjects

S J Foster

Publications and source records attributed to S J Foster.

At least 91 records · Page 5Linked to original sources
PubMed1991

(Methoxyalkyl)thiazoles: a new series of potent, selective, and orally active 5-lipoxygenase inhibitors displaying high enantioselectivity.

(Methoxyalkyl)thiazoles are novel 5-lipoxygenase (5-LPO) inhibitors that are neither redox agents nor iron chelators. Consideration of a hypothetical model of the enzyme active site led to this series which is exemplified by 1-[3-(naphth-2-ylmethoxy)phenyl]-1-(thiazol-2-yl)propy l methyl ether (2d, ICI211965). 2d inhibits cell-free guinea pig 5-LPO activity, LTC4 synthesis in plasma free mouse macrophages, and LTB4 synthesis in rat and human blood (IC50s 0.1 microM, 8 nM, 0.5 microM, and 0.4 microM, respectively) but does not inhibit the synthesis of cyclooxygenase products at concentrations up to 50 microM in macrophages and 100 microM in blood. 2d is orally active in rat (ex vivo ED50 10 mg/kg in blood taken in 1 h after dosing). SAR studies show that high in vitro potency requires methoxy, thiazolyl, and naphthyl groups and depends critically on the substitution pattern. (Methoxyalkyl)thiazoles are chiral. Resolution of 1-methoxy-6-(naphth-2-ylmethoxy)-1-(thiazol-2-yl)indan (2j, ICI216800) shows that (+)-2j is 50-150-fold more potent than (-)-2j in in vitro assays. Thus, (methoxyalkyl)thiazoles are a new series of orally active, selective 5-LPO inhibitors and represent the first class of inhibitors in which inhibition is mediated by specific, enantioselective interactions with the enzyme.

Administration, Oral↗
PubMed1991

Cloning, expression, sequence analysis and biochemical characterization of an autolytic amidase of Bacillus subtilis 168 trpC2.

By use of a functional assay for activity, an autolysin structural gene was cloned on a 3 kb EcoRI DNA fragment from a lambda gt11 expression library of Bacillus subtilis 168 trpC2 genomic DNA. Sequencing of the fragment showed five open reading frames, the central one of which encoded the lytic enzyme as found by subclone activity mapping and its homology to a recently sequenced autolysin gene. The protein had a deduced sequence of 272 amino acids and a molecular mass of 29957 Da. When expressed in Escherichia coli DH5 alpha, the protein was processed to a 21 kDa form, as estimated by renaturing SDS-PAGE. The autolysin was an N-acetylmuramyl-L-alanine amidase and its activity was MgCl2-dependent (20 mM optimum) and LiCl-sensitive. The enzyme could bind to and hydrolyse a wide range of peptidoglycan substrates isolated from Gram-positive bacteria; the binding was also MgCl2-dependent. Initial mapping experiments located the autolysin gene near aroD on the B. subtilis 168 chromosome.

Amino Acid Sequence↗
PubMed1990

Leukotrienes do not regulate interleukin 1 production by activated macrophages.

The objective of this work was to investigate the role of leukotrienes in the production of IL-1 by activated human peripheral blood monocytes and mouse peritoneal macrophages. Using overnight adherent macrophages, stimulation with lipopolysaccharide or zymosan caused a time-dependent increase in IL-1 production. LTC4 was detected and preceded IL-1 production only in zymosan-treated macrophages. Lipopolysaccharide did not stimulate macrophages to produce LTC4. Zymosan-stimulated LTC4 production was inhibited by the lipoxygenase inhibitors, ICI207968 (3.20 microM), nordihydroguaiaretic acid (0.22 microM), phenidone (4.60 microM), REV5901 (0.20 microM), and the Merck 5-lipoxygenase "translocation inhibitor" MK886 (0.02 microM) with IC50 values as shown in parenthesis. However, none of these inhibitors reduced IL-1 production at concentrations which completely inhibited leukotriene synthesis. Taken together, these results do not support a role for leukotrienes in the production of IL-1 by zymosan-activated macrophages.

Animals↗
PubMed1990

Pulling the trigger: the mechanism of bacterial spore germination.

In spite of displaying the most extreme dormancy and resistance properties known among living systems, bacterial endospores retain an alert environment-sensing mechanism that can respond within seconds to the presence of specific germinants. This germination response is triggered in the absence of both germinant and germinant-stimulated metabolism. Genes coding for components of the sensing mechanism in spores of Bacillus subtilis have been cloned and sequenced. However, the molecular mechanism whereby these receptors interact with germinants to initiate the germination response is unknown. Recent evidence has suggested that in spores of Bacillus megaterium KM, proteolytic activation of an autolytic enzyme constitutes part of the germination trigger reaction.

Bacillus megaterium↗
PubMed1990

Selective chiral inhibitors of 5-lipoxygenase with anti-inflammatory activity.

The studies described here, using enantiomers of an optically-active methoxy alkyl thiazole ICI216800 (1-methoxy-6-(naphth-2-yl-methoxyl)-1- (thiazol-2-yl)indane), provide unequivocal evidence for a specific, chiral interaction with 5-lipoxygenase. In accordance with their biochemical efficacy these compounds also demonstrate enantio-specific anti-inflammatory activity in a leukotriene-mediated model of inflammation. This is the first class of compounds for which 5-lipoxygenase inhibition and anti-inflammatory activity have been shown to be mediated via a specific chiral interaction.

Animals↗
PubMed1990

2-substituted indazolinones: orally active and selective 5-lipoxygenase inhibitors with anti-inflammatory activity.

1. This paper describes the pharmacological profile of ICI207968, a novel, orally-active and selective inhibitor of 5-lipoxygenase. 2. Inhibition of leukotriene B4 (LTB4) synthesis by 2-substituted indazolinones was not directly related to redox potential but was critically dependent on the nature of the N2 substituent. 2-(3-Pyridylmethyl)-indazolinone (ICI207968) combined selectivity and oral potency. 3. In several in vitro systems ICI207968 exhibited similar lipoxygenase inhibitory potency (IC50 values from 1.5 microM to 6.0 microM) and was approximately 300 times less potent against cyclo-oxygenase, as measured by inhibition of prostaglandin E2 (PGE2) synthesis. 4. ICI207968 also produced selective lipoxygenase inhibition following oral administration in the rat. ED50 values of 2.5, 10 and 25 mg kg-1 p.o. for inhibition of LTB4 release from A23187-stimulated blood were obtained 1, 3 and 5 h after dosing. The compound did not inhibit PGE2 synthesis at oral doses up to 300 mg kg-1. 5. Co-administration of ICI207968 with arachidonic acid, into rabbit dermis, potently inhibited both plasma extravasation and polymorphonuclear leucocyte (PMNL) infiltration induced by this inflammatory fatty acid. The anti-inflammatory potency of a number of intradermally administered indazolinones, with similar redox potentials, was related to their inhibitory potency against leukotriene generation in blood. Oral administration of ICI207968 (100 mg kg-1) in the rabbit inhibited ex vivo leukotriene generation in blood and arachidonic acid-induced skin inflammation. 6. These data demonstrate that ICI207968 is an orally active and selective inhibitor of 5-lipoxygenase which has anti-inflammatory properties. IC1207968 will be a valuable agent for clarifying the biological roles of leukotrienes and the therapeutic potential of 5-lipoxygenase inhibitors.

Administration, Oral↗
PubMed1989

Acute inflammatory effects of a monocyte-derived neutrophil-activating peptide in rabbit skin.

The inflammatory effects of a monocyte-derived neutrophil-activating peptide (MONAP), purified to homogeneity from lipopolysaccharide-stimulated human peripheral blood monocytes, have been evaluated in rabbit skin. Intradermal injection of MONAP alone caused a mild infiltration of polymorphonuclear leucocytes (PMNL) but did not induce any change in plasma extravasation. When combined with prostaglandin E2(PGE2), MONAP caused a marked and synergistic increase in PMNL infiltration and plasma extravasation into the injected skin sites. The increase in vascular permeability induced by MONAP depended on the presence of circulating PMNL. MONAP is a novel cytokine with pro-inflammatory properties and may have physiological and pathophysiological roles in health and disease.

Animals↗
PubMed1988

Leukotriene B4 and inflammatory disease.

Polymorphonuclear leukocytes (PMNL) are prominent at sites of acute inflammation. Their infiltration is stimulated under pathological conditions by a variety of agents which include bacteria, immune complexes and complement derived chemotactic peptides. Recently attention was focussed on the 5-lipoxygenase product leukotriene B4 (LTB4) which has been demonstrated to induce the key features associated with an acute inflammatory reaction. However, evidence supporting a pro-inflammatory role for LTB4, and therefore the anti-inflammatory efficacy of 5-lipoxygenase inhibitors, is largely circumstantial. Moreover, there are concerns that other chemotactic factors, notably C5a, may compensate for the absence of LTB4. Here we challenge this view and, on the basis of recent experimental and clinical data suggest that LTB4 does not simply duplicate the activity of C5a. Instead we propose that their predominant site(s) of action differ in such a way that they may synergise in mediating PMNL recruitment.

Animals↗
PubMed1988

Current contrast media and ioxilan. Comparative evaluation of vascular pain by aversion conditioning.

Vascular pain caused by contrast media (CM) cannot be quantified by subjective patient reports or manifest pain reactions in experimental animals. Therefore, conditioned taste aversion (CTA), a psychopharmacological method, was used in double-blind femoral arteriography in rats to compare a new nonionic monomeric CM, ioxilan, with iohexol, iopamidol (all at 350 mgI/mL) and 22% sorbitol. A chronically implanted femoral artery catheter was used to inject 0.2 mL/kg body weight. By measuring the intake of water laced with the flavor that thirsty rats had learned to associate with the injection, the degree of aversion, assumed proportional to pain, was determined. Ioxilan (690 mOsm) produced the least pain, followed by iopamidol (810 mOsm), iohexol (844 mOsm) and sorbitol (1410 mOsm). Since all test substances are highly and similarly hydrophilic and nonionic, the intensity of vascular pain must depend on solution osmolality, rather than on chemotoxicity or ionicity. Compounds of the lowest osmolality, ig, ioxilan, elicit the least vascular pain.

Animals↗
PubMed1988

Isomerism in iohexol and ioxilan. Analysis and implications.

Pharmacologically useful contrast media (CM) must be highly water-soluble to form stable supersaturated solutions. Iohexol and ioxilan both contain centers of potential isomerism stemming from the D,L hydroxyalkyls, the carbamoyl substituents, the alkylated anilide nitrogen and the acetylated anilide. The D,L isomers are individual compounds, both highly water-soluble and equally highly hydrophilic. The carbamoyl rotamers result from steric restriction by the adjacent iodines, and are interconvertible at physiologic temperature ranges; only at low temperatures can high field nuclear magnetic resonance (NMR) identify them. The isomers resulting from the alkylated anilide are fixed, but since they can exist only by reference to fixed carbamoyls, they are not relevant at physiologic temperatures. The N-acetyl endo-/exo-isomers are crystallizable from alcoholic solvents and identifiable by high-pressure liquid chromatography (HPLC) and hydrogen-1 (1H) and 13C NMR. They interconvert rapidly in water, forming stable and highly soluble mixtures. All isomers of iohexol or ioxilan, based on HPLC, are similarly highly hydrophilic, and are expected to show low binding to biomacromolecules with a concomitantly high biological tolerance. Since these mixtures are unavoidable, they must be considered a pharmacologic entity.

Chromatography, High Pressure Liquid↗
PubMed1988

Germination-specific cortex-lytic enzyme is activated during triggering of Bacillus megaterium KM spore germination.

Antibodies were raised against purified germination-specific cortex-lytic enzyme (GSLE) from spores of Bacillus megaterium KM which neutralized the ability of GSLE to germinate permeabilized spores. Western blotting of dormant spore and vegetative cell fractions separated by SDS-PAGE demonstrated that GSLE is spore-specific and that greater than 90% of the GSLE is associated with the dormant spore cortex peptidoglycan as a phosphorylated 63kD pro-form, which could only be visualized after lysozyme digestion of the peptidoglycan. During germination, the 63kD pro-form of GSLE is processed to release the active enzyme, which had an apparent molecular weight of 30kD. Inhibitor studies demonstrated that GSLE activation occurs as part of the commitment reaction and thus represents the first-identified enzymatic event to occur during germination triggering. Proteins that cross-react with anti-GSLE sera are present in spore fractions of other species.

Bacillus megaterium↗
PubMed1987

Purification and properties of a germination-specific cortex-lytic enzyme from spores of Bacillus megaterium KM.

Two peptidoglycan-lytic enzyme activities were isolated from spores of Bacillus megaterium KM. Surface-bound lytic enzyme was extracted from dormant spores and hydrolysed a variety of peptidoglycan substrates including isolated spore cortex, but did not cause refractility changes in permeabilized spores. Germination-specific lytic enzyme activity appeared early in germination and had minimal activity on isolated peptidoglycan substrates, but caused refractility changes in permeabilized spores of several Bacillus isolated peptidoglycan substrates, but caused refractility changes in permeabilized spores of several Bacillus species. The germination-specific lytic enzyme was shown to be a heat-sensitive 29 kDa protein with maximal activity at pH 6.5. It catalysed post-commitment muramic acid delta-lactam synthesis and displayed an inhibitor profile similar to that for post-commitment A600 loss. The relationship of the germination-specific enzyme to a recently proposed model of spore germination is discussed.

Bacillus megaterium↗
PubMed1987

Leukotriene B4 metabolism in human leukocytes: fact or artefact?

The object of this study was to investigate the importance of omega oxidation in regulating leukotriene B4 (LTB4) levels in man. In human polymorphonuclear leukocytes metabolism of LTB4 was rapid but was critically dependent on PMN number: greater than 1.5 X 10(6) PMN/ml were required. Metabolism of LTB4 was blocked in the presence of plasma. In whole blood and in PMN-rich rheumatoid synovial fluids no significant metabolism of LTB4 was detected within 30 min at 37 degrees C. We conclude that LTB4 metabolism at inflamed sites will be regulated both by cellular content and the degree of plasma exudation. In most pathological conditions rapid exchange with the micro-vasculature will be more important than metabolism in limiting LTB4 levels.

Arthritis, Rheumatoid↗
PubMed1987

Trimethylselenonium ion.

Explore the source record for details and available documents.

Chromatography, High Pressure Liquid↗
PubMed1987

Leukotriene B4 and prostaglandin E2 mediate the inflammatory response of rabbit skin to intradermal arachidonic acid.

1. Acute inflammation was induced in rabbit skin by intradermal injection of arachidonic acid. 2. Inflammation was assessed by the local accumulation of intravenously-injected 125I-serum albumin (plasma extravasation) and histologically (polymorphonuclear leucocyte, PMNL infiltration). 3. Leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) were extracted from skin and fractionated using C18 mini-columns. They were quantitated by specific radioimmunoassays and authenticated by reversed-phase high performance liquid chromatography analysis. 4. Maximally elevated levels of LTB4 and PGE2 were detected in skin 5 min after arachidonic acid injection. At subsequent times the eicosanoid content of the skin decreased. 5. The decrease in the eicosanoid content of the skin was due to rapid clearance (t 1/2 approximately 5 min) via the microvasculature and not a consequence of metabolism. 6. The concentration of LTB4 and PGE2 measured in inflamed skin was sufficient to account for the plasma extravasation and PMNL infiltration induced by arachidonic acid. The model therefore is useful for evaluating the anti-inflammatory efficacy of inhibitors of arachidonic acid metabolism including 5-lipoxygenase inhibitors. 7. The consequences of the rapid clearance of LTB4 from inflammatory sites are discussed with respect to its measurement in inflammatory disease and its role as an acute inflammatory mediator.

Animals↗