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Biomedical subjects

C M Edwards

Publications and source records attributed to C M Edwards.

At least 55 records · Page 3Linked to original sources
PubMed1997

Pharmacological activity of feverfew (Tanacetum parthenium (L.) Schultz-Bip.): assessment by inhibition of human polymorphonuclear leukocyte chemiluminescence in-vitro.

The bioactivity of feverfew (Tanacetum parthenium) leaf extracts has been analysed, by use of a human polymorphonuclear leukocyte (PMNL) bioassay, to assess the relative contributions of solvent extraction and parthenolide content to the biological potency of the extract. Extracts prepared in acetone-ethanol (system 1) contained significantly more parthenolide (mean +/- s.d. 1.3 +/- 0.2% dry leaf weight) than extracts in chloroform-PBS (phosphate-buffered saline; system 2; 0.1 +/- 0.04% dry leaf weight) or PBS alone (system 3; 0.5 +/- 0.1% dry leaf weight). Extract bioactivity, measured as inhibition of phorbol 12-myristate 13-acetate-induced, 5-amino-2,3-dihydro-1,4-phthalazinedione (luminol)-enhanced PMNL, chemiluminescence, followed a similar trend. Extracts inhibited phorbol 12-myristate 13-acetate-induced oxidative burst by amounts which, if solely attributable to parthenolide, indicated parthenolide concentrations for the respective solvent systems of 2.2 +/- 0.6%, 0.2 +/- 0.1% and 0.9 +/- 0.1% dry leaf weight. The mean ratio of parthenolide concentration to the parthenolide equivalent/PMNL-bioactivity value, for acetone-ethanol and PBS extracts were both 1:1.7. Parthenolide, although a key determinant of biological activity for T. parthenium leaf extracts based on the PMNL-bioassay, seems not to be the sole pharmacologically-active constituent. The identical and elevated bioactivity-parthenolide ratios for both organic and aqueons-phase leaf extracts suggest that a proportion of the other bioactive compounds have solubilities similar to that of parthenolide.

Chromatography, High Pressure Liquid↗
PubMed1997

Cardiovascular and pancreatic endocrine responses to glucagon-like peptide-1(7-36) amide in the conscious calf.

Intravenous infusions of glucagon-like peptide-1(7-36) amide (GLP-1; 35 pmol min-1 kg-1 for 10 min) produced a significant rise in mean heart rate, without significant change in mean aortic blood pressure, together with a significant rise in mean arterial plasma insulin, but not in plasma pancreatic glucagon or pancreatic polypeptide concentration, in conscious calves given exogenous glucose (30-60 micromol min-1 kg-1 i.v.). The insulinotropic effect was eliminated in the presence of exogenous amino acids (0.03 mmol min-1 kg-1 i.v.). It was not affected predictably by blocking the synthesis of nitric oxide or by the simultaneous administration of the established incretin factor gastrin-releasing peptide (GRP). Whereas GLP-1 produced a statistically significant rise in plasma insulin concentration in these animals, it was much less effective than GRP in this respect, when given by continuous i.v. infusion.

Amino Acids↗
PubMed1997

Neuropeptide Y induced feeding in the rat is mediated by a novel receptor.

There are now six recognized neuropeptide Y (NPY) receptor subtypes (Y1-Y4 and two recently cloned distinct receptors labeled Y5), of which Y1 and one of the Y5's have been suggested could mediate the effect of NPY on feeding. The fragments NPY(2-36) and NPY(3-36), which bind Y1 only poorly, were injected intracerebroventricularly (icv) and found to have similar dose-response relationships to NPY in the stimulation of feeding. However NPY (13-36), which stimulates both Y2 and Y5, caused no increase in food intake, even at high doses. Maximal stimulation with the classical Y1 agonist [Pro34]-NPY produced only 50% of the maximum effect of NPY itself despite fully inhibiting adenylyl cyclase activity in vitro in a Y1 system. The novel fragment [Pro34]-NPY(3-36) is as effective at stimulating food intake as the classical Y1 analogue [Pro34]-NPY but bound to the Y1 receptor with only 1/20th of the affinity of NPY and failed to inhibit adenylyl cyclase through this receptor. [Pro34]-NPY(3-36) is therefore a relatively appetite-selective ligand. Coadministration of high dose NPY(13-36) and [Pro34]NPY did not enhance feeding compared with [Pro34]-NPY alone. In addition, the NPY Y1 receptor antagonist BIBP-3226, which does not bind Y2, Y4, or Y5 receptors, significantly reduced NPY induced feeding. These results indicate that the feeding effect of icv NPY involves a novel receptor and that it is functionally distinct from the recognized receptor subtypes.

Adenylyl Cyclases↗
PubMed1997

Changes in cell biochemistry in response to culture of protoplasts with oxygenated perfluorocarbon.

Superoxide dismutase (superoxide oxidoreductase; EC 1.15.1.1; SOD) was measured in enzymatically isolated protoplasts of Salpiglossis sinuata following culture in aqueous nutrient medium overlaying oxygen-gassed perfluorodecalin (Flutec PP6; BNFL Fluorochemicals, UK). SOD was extracted from harvested, lysed protoplast-derived cells after 1, 3, 7 and 14 days of culture and assayed spectrophotometrically. Protoplasts cultured with oxygenated PFC (+/- s.e.m, n = 5) showed significant increases in mean SOD activity to 4.2 +/- 0.1 U after 1 day (P < 0.05) and 9.3 +/- 0.7 U after 3 days (P < 0.01), with a fall in mean SOD after 7 days (5.1 +/- 0.9 U), similar to control. The decrease in SOD after 7 days correlated closely with a progressive fall in pO2 in the PFC phase over the same period. In contrast, control protoplasts (medium alone) or protoplasts cultured in medium overlaying non-oxygenated PFC showed no significant changes in mean SOD activity over the 14-day culture assessment period.

Cells, Cultured↗
PubMed1997

Effects of a novel perfluorocarbon emulsion on neutrophil chemiluminescence in human whole blood in vitro.

The effects have been studied of a novel perfluorochemical (PFC) emulsion (18.5% perfluorodecalin, 1.5% perfluorodimorpholine propane, 2.5% lecithin) on phorbol 12-myristate 13-acetate (PMA; 100 micrograms ml-1)-induced neutrophil chemiluminescence in citrated human whole blood in vitro. A transient, dose-dependent, decrease in chemiluminescence, to a maximum of 54% after 12 min (P < 0.05), occurred when blood was pre-incubated with 10-40 microliters of the PFC emulsion, compared to saline controls. The mean (+/- s.e.m., n = 6) chemiluminescence of neutrophils incubated with 30 microliters emulsion at 12 min following PMA stimulation (9.5 +/- 1.3 mV) was significantly lower (P < 0.05) than control (24.2 +/- 2.2 mV). Incubation of blood with lecithin up to 16 mg ml-1 and Pluronic F-68 or Pluronic PE 6800 up to 65 mg ml-1 did not affect chemiluminescence.

Anions↗
PubMed1997

Novel fluorinated surfactants for perfluorochemical emulsification: biocompatibility assessments of glycosidic and polyol derivatives.

A novel series of fluoro-surfactants, derived from glycosides (monosaccharides) or polyols (ureas or carbamates), have been produced for use in respiratory gas-carrying perfluorochemical emulsions. Compounds were synthesised via simple, but highly selective, routes using highly fluorinated isocyanates with amino alcohols, polyethoxylated alcohols and partially protected sugars at anomeric carbon; yields were 88-95%. Resultant compounds were perfluoroalkylated with hydroxylic "head" groups. The biocompatibility of surfactants with human blood in vitro was assessed using a conventional haemolysis test. Compounds showing insignificant haemolysis at up to 10 g l-1 were further evaluated (i) for their effects on neutrophil chemiluminescence, and (ii) in a human platelet aggregation assay. Some fluoro-surfactants inhibited spontaneous platelet aggregation, in blood anti-coagulated with hirudin, at concentrations of 0.01% (w/v), suggesting possible applications as antithrombotic agents.

Ampholyte Mixtures↗
PubMed1997

Effects of the co-polymer surfactant, Pluronic F-68, on platelet aggregation in human whole blood.

The effects have been studied of Pluronic F-68 on platelet aggregation in human whole blood. The median spontaneous platelet aggregation in normal blood (n = 15) was 18.4% [interquartile range (IQ) = 10.5-24.2%]. Commercial grade Pluronic F-68 significantly (P < 0.05) reduced platelet aggregation at 7.3 microM (median = 8.4%, IQ = 3.9-13.4; n = 12) and almost eliminated aggregation at concentrations of > 58 microM (median = 2.0%, IQ = 0.0-3.5). Similar results were obtained with a silica gelpurified Pluronic F-68 fraction (n = 3). Pluronic F-68 also accelerated the rate of platelet dis-aggregation in blood treated with 0.3, 1.0 or 3.0 mM adenosine di-phosphate. These results suggest that the therapeutic effects of Pluronic F-68 in ischaemic injury may be due, in part, to inhibition of platelet aggregation in the microcirculation. The beneficial effects of tissue perfusion with oxygen-carrying perfluorochemical emulsions, containing Pluronic F-68, may also involve direct effects of the surfactant on platelets.

Adenosine Diphosphate↗
PubMed1996

A role for glucagon-like peptide-1 in the central regulation of feeding.

The sequence of glucagon-like peptide-1 (7-36) amide (GLP-1) is completely conserved in all mammalian species studied, implying that it plays a critical physiological role. We have shown that GLP-1 and its specific receptors are present in the hypothalamus. No physiological role for central GLP-1 has been established. We report here that intracerebroventricular (ICV) GLP-1 powerfully inhibits feeding in fasted rats. ICV injection of the specific GLP-1-receptor antagonist, exendin (9-39), blocked the inhibitory effect of GLP-1 on food intake. Exendin (9-39) alone had no influence on fast-induced feeding but more than doubled food intake in satiated rats, and augmented the feeding response to the appetite stimulant, neuropeptide Y. Induction of c-fos is a marker of neuronal activation. Following ICV GLP-1 injection, c-fos appeared exclusively in the paraventricular nucleus of the hypothalamus and central nucleus of the amygdala, and this was inhibited by prior administration of exendin (9-39). Both of these regions of the brain are of primary importance in the regulation of feeding. These findings suggest that central GLP-1 is a new physiological mediator of satiety.

Animals↗
PubMed1996

Early measurement of interstitial fibrosis predicts long-term renal function and graft survival in renal transplantation.

This study investigated the relationships between renal allograft interstitial fibrosis, renal function and graft survival. A total of 107 consecutive renal transplant recipients immunosuppressed with cyclosporin were studied. Needle core transplant biopsies were performed before operation and at 1, 6 and 12 months after transplantation. Allograft fibrosis was assessed by histomorphometric analysis of graft interstitial volume fraction. Renal function was measured by isotopic glomerular filtration rate (GFR) measurement at the same time points. Interstitial volume fraction was already high in preperfusion biopsies, significantly increased with time but stabilized at 6 months after transplantation. GFR correlated negatively with interstitial volume fraction at 6 months (P = 0.05). Interstitial volume fraction at 1 month was not a useful predictor of subsequent graft survival but for allografts surviving to 6 months an interstitial volume fraction above 25 per cent predicted significantly poorer survival (P = 0.04). It provides an objective measure of chronic allograft damage and may prove to be a useful surrogate endpoint in the study of therapeutic intervention.

Biopsy, Needle↗
PubMed1996

Measurement of the flux of lead from bone to blood in a nonhuman primate (Macaca fascicularis) by sequential administration of stable lead isotopes.

To better understand the kinetics of the transfer of lead from bone to blood, we have developed and tested a method in which sequential doses of lead, each enriched with a different stable isotope, were administered in a nonhuman primate Macaca fascicularis whose skeleton had been previously labeled with lead of known isotopic composition. Lead isotopic ratios of blood and bone samples, analyzed by thermal ionization mass spectrometry (TIMS), were unmixed by isotope dilution techniques. The first label administered allows the contribution from historical bone stores to be measured. Subsequent labels allow measurement of both the historical bone stores and the previous labels that have become recently incorporated into bone. The method may be extended to studies of bone lead mobilization in pregnancy, lactation, menopause, or in disease states such as postmenopausal osteoporosis.

Animals↗
PubMed1996

The relative influence of delayed graft function and acute rejection on renal transplant survival.

Three hundred and eight cadaveric renal transplants were analysed to establish the effects of acute rejection in the first 90 days and delayed graft function (DGF) on graft outcome. There were 120 patients (39%) with no DGF and no rejection (group 1), 101 patients (33%) with rejection but no DGF (group 2), 41 patients (13%) with DGF but no rejection (group 3) and 46 patients (15%) with both rejection and DGF (group 4). The actuarial 4-year graft survival rates for groups 1,2,3 and 4 were 78.3%, 65.4%, 60.1% and 40.4%, respectively. The acute rejection rate was 101/221 (46%) in patients with initial graft function compared with 46/87 (53%) for those with DGF (chi 2 = 1.02, P = 0.31). Cox stepwise logistic regression analysis demonstrated that DGF was a more powerful predictive factor for poor graft survival (P = 0.001) than acute rejection occurring in the first 90 days post-transplant (P = 0.034). Further efforts at improving graft outcome should concentrate on reducing the incidence of DGF.

Acute Disease↗
PubMed1995

Synthesis of 4"-deoxy motilides: identification of a potent and orally active prokinetic drug candidate.

As an approach to discovering highly potent motilides with oral activity, novel 4"-deoxy derivatives of 8,9-anhydroerythromycin 6,9-hemiacetal were designed, synthesized, and evaluated for their gastrointestinal prokinetic activities. These compounds were orders of magnitude more potent than their 4"-hydroxy analogs in inducing smooth muscle contractions in an in vitro rabbit duodenal assay. Removal of the 12-hydroxy group, which was aimed at improving oral bioavailability, also afforded further potentiation in in vitro activity, leading to the identification of 8,9-anhydro-4"-deoxy-3'-N-desmethyl-3'-N-ethylerythromycin B 6,9-hemiacetal (ABT-229) as a potential prokinetic drug. ABT-229 was > 300,000 times more potent than erythromycin in vitro and had 39% oral bioavailability in dog compared to its 4",12-dihydroxy congener (EM-523), which was only 400 times more potent than erythromycin and had relatively low (1.4%) oral bioavailability.

Administration, Oral↗
PubMed1995

Vascular and hormonal responses to arginine: provision of substrate for nitric oxide or non-specific effect?

1. The vascular and hormonal effects of L- and D-arginine were compared in healthy subjects and in patients with insulin-dependent diabetes mellitus or untreated essential hypertension. 2. Infusion of L- or D-arginine (40 mumol/l) in the forearm vascular bed, sufficient to increase the local concentration approximately 20-fold, had no effect on blood flow or the vasodilator response to acetylcholine (30 and 100 nmol/min) in patients with insulin-dependent diabetes (n = 7) or essential hypertension (n = 7), or in age- and sex-matched control subjects (n = 7 in both groups). 3. Systemic infusion of 10 g of L-arginine (n = 5) or D-arginine (n = 3) increased plasma concentration of arginine approximately 20-fold without altering supine or erect haemodynamics. Increases in plasma insulin, prolactin and glucagon were seen with both enantiomers. The stereopurity of arginine was confirmed in a cell-culture assay system. 4. We conclude that, in healthy subjects and patients with essential hypertension or insulin-dependent diabetes, synthesis of nitric oxide within the vasculature is not limited by substrate availability. At high concentrations of arginine, non-stereospecific effects, including alterations in hormone concentration, occur. It remains to be determined whether these non-stereospecific hormonal changes might contribute to certain haemodynamic effects of arginine.

Adult↗
PubMed1994

Cyclosporin, nifedipine and gingival hyperplasia: a randomized controlled study.

Nifedipine increases the frequency and severity of gingival hyperplasia associated with CyA therapy in renal transplant recipients and this effect appears to be independent of whole-blood CyA levels. De novo malignancies have been reported arising in areas of gingival hyperplasia, in a group already at high risk of malignancy. Patients receiving CyA and nifedipine should receive advice regarding the need for strict oral hygiene to control the initial development of gingival hyperplasia, with severe cases being promptly referred for gingivectomy and histological examination.

Calcium Channel Blockers↗