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G Burton

Publications and source records attributed to G Burton.

At least 37 records · Page 2Linked to original sources
PubMed2000

Mechanism of action of the potent sodium-retaining steroid 11, 19-oxidoprogesterone.

We have demonstrated previously that a planar conformation of the molecular frame is required for steroids to acquire optimal sodium-retaining activity and binding properties to the mineralocorticoid receptor (MR). One of the most active sodium-retaining compounds tested in those studies was 11, 19-oxidoprogesterone. Despite its biological potency, the relative affinity of 11,19-oxidoprogesterone for the MR is 5-fold lower than that of 21-deoxycorticosterone and 10-fold lower than aldosterone. Such a discrepancy may be assigned to uncommon biopharmacological properties of this synthetic steroid or an unusual molecular mechanism of action. In this work, we studied the biopharmacological and mechanistic features of 11,19-oxidoprogesterone. We show that both the pharmacokinetic properties of 11,19-oxidoprogesterone and its ability to transform and translocate the MR into the nucleus are undistinguishable from aldosterone. However, the capability of the serine/threonine phosphatase inhibitor tautomycin to impair nuclear translocation of the aldosterone-MR complex is not observed for the 11,19-oxidoprogesterone-MR complex. In addition, the binding properties of both steroids are differentially affected by modification of crucial lysyl residues of the MR. Kinetic studies performed on the aldosterone-MR complex in the presence of low concentrations of oxidopregnane suggest that 11,19-oxidoprogesterone may bind to the MR in a different binding site from the aldosterone binding pocket. Consistent with this postulate, a biologically inactive dose of 0.6 ng of oxidopregnane is able to potentiate the mineralocorticoid effect of a suboptimal dose of aldosterone.

Aldosterone↗
PubMed1999

The glucocorticoid properties of the synthetic steroid pregna-1,4-diene-11beta-ol-3,20-dione (deltaHOP) are not entirely correlated with the steroid binding to the glucocorticoid receptor.

The natural steroid 11beta-hydroxyprogesterone is not only a modulator of 11beta-hydroxy-steroid dehydrogenase activity, but also an efficient inducer of tyrosine aminotransferase activity in hepatocytes. In contrast with the low affinity for the mineralocorticoid receptor. 11beta-hydroxyprogesterone binds well to both the glucocorticoid receptor and the carrier protein transcortin. It is accepted that the introduction of a 1:ene double bond into 3-keto 4:ene steroids increases the glucocorticoid potency, so that 3-keto-1,4:diene steroids show improved chemical stability and are more potent glucocorticoids than their respective 4:ene analogs. The steroid pregna-1,4-diene-11beta-ol-3,20-dione (deltaHOP) had previously been described as an anti-inflamatory compound and an inhibitor of macromolecular biosynthesis in thymocytes and lymphocytes. In such studies, deltaHOP also exhibited some particular glucocorticoid properties which made it attractive as a tool for the study of the mechanism of action of glucocorticoids. In the present paper we show that deltaHOP possesses some classical biological actions of glucocorticoids such as deposition of glycogen in rat liver, induction of TAT activity in hepatocytes, and inhibition of the uptake of leucine and thymidine by thymocytes. It also exhibits minimal sodium-retaining properties. Consistent with these biological effects, deltaHOP shows a 70 times lower relative binding affinity for the mineralocortioid receptor than aldosterone, but a reasonable affinity for the glucocorticoid receptor, and is as efficient as dexamethasone in dissociating the 90 kDa heat shock protein from the glucocorticoid receptor heterocomplex. However, the inhibition of the uptake of amino acids and nucleotides observed in the presence of deltaHOP is not efficiently blocked when thymocytes are coincubated in the presence of steroids with known antiglucocorticoid activity. deltaHOP is similarly inefficient in inducing chloramphenicol-acetyl transferase activity in cells transfected with a plasmid that possesses two canonical glucocorticoid-responsive elements. Unlike most glucocorticoids, deltaHOP does not induce the fragmentation of DNA in a regular pattern characteristic of apoptosis and it does not reduce thymus weight. This unusual dissociation of glucocorticoid parameters makes deltaHOP a useful tool to discriminate between mechanisms of action by which steroids can exert their biological effects.

Animals↗
PubMed1999

7-Hydroxywithanolides from datura ferox

Three new withanolides were isolated from leaves of Datura ferox. Their structures were established as (17R,20S,22R)-5alpha,6alpha, 7beta,12alpha-tetrahydroxy-1-oxowitha-2,24-dienolide (1), (17R,20S, 22R,24S,25S)-24,25-epoxy-5alpha,6alpha,7beta, 12alpha-tetrahydroxy-1-oxowitha-2-enolide (2), and (17R,20S, 22R)-5alpha,6alpha-epoxy-7alpha-hydroxy-1,12-dioxowitha-2, 24-dienolide (3), using spectroscopic methods (NMR, MS) and molecular modeling.

Journal Article↗
PubMed1999

18,20-Hemiacetal-type and other withanolides from dunalia brachyacantha

Two Dunalia brachyacantha specimens collected at different locations in Argentina were investigated separately. The 18,20-hemiacetal-type withanolides (17S,20R,22R,24S,25R)-4beta-acetyloxy-5beta,6beta:18, 20-diepoxy-18-hydroxy-1-oxowitha-2-enolide (1) and (17S,20R, 22R)-4beta-acetyloxy-5beta,6beta:18, 20-diepoxy-18-hydroxy-1-oxowitha-2,24-dienolide (2) were isolated from the first collection, both as mixtures epimeric at C-18. The second collection contained instead (17R,20S,22R)-5beta, 6beta-epoxy-4beta,16alpha-dihydroxy-1-oxowitha-2,24-dienolide (3); (17R,20S,22R)-5beta,6beta-epoxy-4beta,18-dihydroxy-1-oxowitha-2, 24-dienolide (4), and (17R,20S,22R)-5beta,6beta-epoxy-4beta, 16alpha-dihydroxy-1,18-dioxowitha-2,24-dienolide (5). All five new withanolides (1-5) bear an A and B ring substitution pattern similar to that of withaferin A, and their structural elucidation was achieved by spectroscopic techniques.

Journal Article↗
PubMed1999

In-vivo measurement of intrauterine gases and acid-base values early in human pregnancy.

A new multiparameter sensor that combines electrochemical and fibre-optic technology was used for continuous in-vivo investigation of pH, carbon dioxide partial pressure (PCO(2)), oxygen partial pressure (PO(2)), bicarbonate concentration (HCO(3)(-)), base excess, and oxygen saturation (O(2)Sat) early in human pregnancy. The sensor was inserted into the amniotic cavity and the placental bed of 16 pregnancies at 10-15 weeks gestation, before termination under general anaesthesia. Amniotic fluid and retroplacental blood from the same site were also aspirated and analysed by means of cartridges and a portable blood gas analyser. Eleven series of measurements were obtained. The variation in measurements over the 5 min of monitoring was </=10% for all parameters. The sensor was damaged during insertion into the amniotic cavity in one case and in the placental bed in four cases. Measurements of PO(2) in both the amniotic cavity and the placental bed and of pH in the placental bed were higher using the cartridges than in vivo. The results indicated that in-vivo monitoring of fetoplacental gas and acid-base with a sensor is stable and accurate. Such technology will be helpful in improving our understanding of the fetoplacental metabolism in normal and complicated pregnancies.

Acid-Base Equilibrium↗
PubMed1999

An open study of the bladder neck support prosthesis in genuine stress incontinence.

OBJECTIVE: To determine the proportion of unselected women with genuine stress incontinence in whom a bladder neck support prosthesis could be fitted successfully by three gynaecologists with no prior knowledge of the device, and to measure efficacy of the device. DESIGN: Prospective interventional study. SETTING: Two metropolitan urodynamic units. SAMPLE: Eighty women with genuine stress incontinence. MAIN OUTCOME MEASURES: Average number of leaks per day on a frequency volume chart, average number of pads worn per day, urine loss on a one-hour pad test, and urine flow rate. RESULTS: Of the 80 recruits, 11 had exclusion criteria and four could not be fitted at the first visit. Of 65 participants, 39 (58%) withdrew from the study before week four. In 20 of 39 women (51%) post-surgical scarring made fitting difficult, and six (15%) withdrew for unrelated personal or medical reasons. In five women (13%) the device was never effective; six withdrew because of adverse events and two required devices that were larger or smaller than those presently available. Thus 38 of 65 participants (58%) could be fitted by the three gynaecologists. Of 26 women who wore the device for four weeks, median leaks per day fell from 2.5 (interquartile range (IQR) 1.9-4.6) to 1.0 (IQR 0-2); median number of pads per day fell from 1.5 (IQR 0.5-3) to 0 (IQR 0-1); and median pad test loss fell from 19 g/h (IQR 8-49) to 2 g/h (IQR 0-8). Sixteen of these 26 patients (62%) achieved objective success, six (23%) were socially continent, one failed to respond and three declined to complete all outcome measures. Urine flow rates revealed no evidence of outflow obstruction. At the sixth month, 18 of 26 patients (69%) were wearing the device successfully; 15 of these women continued to the 12th month, and all but one were objectively dry. CONCLUSIONS: The bladder neck support prosthesis is a useful addition to the range of treatments available for the management of genuine stress incontinence, but may be difficult to fit in women who are oestrogen-deprived or have undergone multiple surgical procedures. The demands of the trial protocol were found to be onerous by frail elderly women.

Aged↗
PubMed1998

Benzothiopyran-4-one based reversible inhibitors of the human cytomegalovirus (HCMV) protease.

A novel class of CMV protease inhibitors based on a benzothiopyran-S,S-dioxide nucleus has been discovered. Enzyme kinetic data supports a reversible mode of inhibition for a representative member of this class, 2-(3-pyridyl-N-oxide)benzothiopyran-4-one-S,S-dioxide, 1. Experiments in the presence and absence of the disulfide reducing agent DTT suggest that the inhibition by 1 is not due to oxidative inactivation of the enzyme. Also presented are results of some SAR studies of the benzothiopyranone ring system.

Amino Acid Sequence↗
PubMed1998

New Hydroxylated Withanolides from Salpichroa origanifolia

From the leaves of Salpichroa origanifolia three new withanolides, (20S,22R,24S,25S,26R)-5alpha,6alpha:22,26:24,25-triepoxy-15,26-dihydroxy-17(13-->18)-abeo-ergosta-2,13,15,17-tetraen-1-one (salpichrolide G, 1), (20S,22R,24S,25R)-5alpha,6alpha:22,26-diepoxy-24,25,26-trihydroxy-17(13-->18)-abeo-ergosta-2,13,15,17-tetraen-1-one (salpichrolide H, 2), and (20S,22R,25S)-5alpha,6alpha:22,26-diepoxy-25,26-dihydroxy-17(13-->18)-abeo-ergosta-2,13,15,17,23-pentaen-1-one (salpichrolide I, 3), were isolated and characterized by spectroscopic methods and with the aid of molecular modeling. The latter two compounds were obtained as an epimeric mixture at C-26.

Journal Article↗
PubMed1998

The use of esters as prodrugs for oral delivery of beta-lactam antibiotics.

It is apparent that the sequence of events that has been followed in the approach to the discovery and development of a new beta-lactam prodrug has been similar in many of the case histories we have studied and indeed similar to the approach we have followed. Initially, we select a suitable series of prodrug moieties, which either comprises totally novel structures or is deduced from the data bases available (bearing in mind reports of potential toxicity) or both. The successful preparation of these prodrugs and the studies undertaken to ensure they are of known purity and stability is not easy and, as would be expected, is the initial go/no-go decision. Usually, the next stage has involved the assessment of whether or not bioavailability of the parent molecule is increased after administration of the prodrug ester by gavage to laboratory animal species. The selection of which species to use has very often been made according to which has the most information available in those particular laboratories and in the literature. It is this process that can be dishearteningly misleading as was demonstrated in Table IV and Fig. 1. Increasing the range of animal species does not lead to a better ability to predict bioavailability in humans. Hydrolysis studies are important to ensure that any novel prodrug will hydrolyze in human tissues, and also in the clarification of why a particular prodrug is not performing as expected in animals. After selection, it is essential to determine where and how rapidly hydrolysis takes place in the animal species to be used for safety evaluation prior to the first bioavailability studies in humans. The assessment of absolute oral bioavailability has not always been undertaken. This would seem critical for studies in not only the selected animal species but also in humans. In the absence of these data it is difficult to judge whether oral uptake can be increased further by modifying the ester moieties and at the development stage to determine whether or not modifications in formulation could increase bioavailability. When the prodrug is being developed for an injectable beta-lactam already available for humans, there would be no problem, but it would be an important consideration during the development of an entirely novel beta-lactam antibiotic for which no parenteral data are available in humans. Animal data are not totally predictive. The development of prodrugs is not easy, as a consequence of species differences in the properties of the prodrug superimposed on those of the parent compound during the evaluation. However, technical advances have enabled us to assay concentrations more precisely, determine basic physicochemical properties more efficiently, understand absorption processes by the use of in vitro systems, and analyze data far more comprehensively by the use of ever-evolving computer software. The prodrug approach to increasing the oral bioavailability of beta-lactam antibiotics has provided clinically valuable agents and continues. Despite the inherent difficulties, knowledge gained over the years, of the relationships between physicochemical and biological properties of the parent compound and the intact prodrug ester, has contributed to the design of novel prodrugs and a number of novel auxiliaries have been developed.

Animals↗
PubMed1998

Influence of calf serum on glucocorticoid-responses of certain progesterone derivatives.

UNLABELLED: The following in vitro glucocorticoid (GC) parameters of progesterone (P), 1-ene progesterone (deltaP), 11beta-hydroxyprogesterone (HOP), 11beta-1-ene progesterone (deltaHOP) and dexamethasone (Dexa) were assayed in the presence or absence of bovine calf serum (BCS): binding to thymus cytosol, dissociation of the glucocorticoid receptor (GR)-heat shock protein 90 (hsp90) complex (diss.), tyrosine aminotransferase (TAT) induction in hepatocytes and the inhibition of 3H-uridine and 35S-methionine uptake by thymocytes. Without BCS, steroids were in most cases active in this general order: Dex > deltaHOP > HOP > deltaP > P. BCS abolished all activities in P and deltaP, but left them unaltered in all other steroids, except diss. in HOP, which diminished intermediately. Binding of P, deltaP, HOP and deltaHOP to GR and CBG paralleled their in vivo activating effects on glycogen deposition. CONCLUSIONS: in this steroid series, BCS, but not CBG, inhibits GC responses of P and deltaP. 11-Beta hydroxylation frees those molecules from the inhibitory effects of BCS.

Adrenalectomy↗
PubMed1998

Perceiving the width and height of a hand-held object by dynamic touch.

The haptic perceptual sybsystem of dynamic touch is prominent in manipulating and transporting objects, providing a nonvisible awareness of their linear dimensions. The hypothesis that perceptions of object width and height by dynamic touch are different functions of the inertia tensor is addressed. In two experiments heights and widths of nonvisible wielded objects were judged separately. Experiment 1 used solid rectangular parallelepipeds of different sizes; Experiment 2 used objects of identical mass and linear dimensions but nonidentical inertia ellipsoids. Width and height perceptions of comparable reliability and accuracy were found to vary as distinct functions of the objects' inertial eigenvalues. Discussion focused on the notion of tangible shape and on the selectivity of attention within dynamic touch.

Hand↗
PubMed1998

Novel C-2 substituted carbapenem derivatives. Part IV. Synthesis and biological activity of five membered heteroaromatic derivatives.

The synthesis, antibacterial activity, and stability to human dehydropeptidase-1 (DHP-1) of a novel series of (5R,6S)-6-[(1R)-1-hydroxyethyl]-2-heterocyclylcarbapen-2-em-3-carb oxylates are described. Of the compounds investigated 1,5-disubstituted pyrazol-3-yl and 3-substituted isoxazol-5-yl derivatives have the best combination of antibacterial activity and stability to DHP-1. They are particularly active against community-acquired respiratory tract pathogens and have stabilities to DHP-1 superior to that of meropenem.

Carbapenems↗
PubMed1997

Vascular estrogen receptors and endothelium-derived nitric oxide production in the mouse aorta. Gender difference and effect of estrogen receptor gene disruption.

The present study was designed to test the hypothesis that estrogen receptors (ER) in the blood vessel wall play a role in the modulation of the release of endothelium-derived nitric oxide (EDNO). Both basal and stimulated release of EDNO were determined in aortic rings isolated from female and male wild-type and male homozygous estrogen receptor knock-out (ERKO) mice. 125I-17beta-estradiol binding in aortic tissue showed significantly more high affinity cytosolic- nuclear-binding sites in male compared with female wildtype mice. Estrogen receptor transcripts were present in the aorta of male wild-type mice, but they were absent in male ERKO animals. Basal release of EDNO (determined by endothelium-dependent contraction caused by NG-nitro-arginine) was significantly higher in aorta of wild-type male mice compared with wild-type female mice, and significantly lower in the aorta of male ERKO compared with male wild-type mice. Acetylcholine-induced endothelium-dependent relaxation was similar in all groups studied. No difference was observed in the activity of calcium-dependent nitric oxide synthase in homogenates of lungs and brain taken from male wild-type and ERKO mice. These studies show a significant association between the number of estrogen receptors and basal release of EDNO in the aorta of mice, and suggest that decreased vascular estrogen receptor number may represent a novel risk factor for cardiovascular diseases.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1997

Features of the shuttle pair 11 beta-hydroxyprogesterone-11-ketoprogesterone.

11 beta-hydroxyprogesterone (HOP) and 11-ketoprogesterone (KP) are reversible components of a shuttle pair whose interconversion in rat liver is catalyzed by isoform-1 of 11 beta-hydroxysteroid dehydrogenase. Kidneys also produce this interconversion. The present study was carried out to investigate the shuttle pair and its components in the rat. As in corticosterone/11-dehydrocorticosterone, oxidation is more effective at an alkaline pH, while reduction prevails at a neutral pH. Moreover, both reactions are inhibited by the detergent 3-[(3-cholamido propyl)-dimethylammonio]-1-propane-sulphonate (CHAPS). However, at variance with the 11-ketosteroids cortisone (E) and 11-dehydrocorticosterone (A) thought to be "inactive," KP has slight direct Na(+)-retaining properties, and it, as well as HOP, induces glucocorticoids (11 beta-hydroxycorticoids) to retain sodium. 11-ketoprogesterone exhibits 17 times better affinity for native type 1 mineralocorticoid receptor than HOP and a 3-fold affinity for partially purified (transcortin free) mineralocorticoid receptor. However, KP, in contrast to HOP, binds only weakly to transcortin, not at all to glucocorticoid receptor, and requires reduction at C11 for tyrosine aminotransferase (TAT) induction.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1997

Treatment of recurrent malignant glioma with BCNU-fluosol and oxygen inhalation. A phase I-II study.

OBJECTIVES: To evaluate the toxicity and response rate following BCNU with oxygen inhalation and escalating dosages of fluosol administered to patients with radiographic progression of malignant glioma after definitive surgery and radiotherapy. METHOD: This single arm, phase I-II multicenter trial, enrolled 99 patients with malignant gliomas recurrent after definitive surgery and radiotherapy. All patients received a fixed dose (200 mg/m2) of BCNU along with 100% oxygen and fluosol, a perfluorochemical. Fluosol doses were escalated between patients (150, 275, 400 and 600 ml/m2). Treatment was repeated every 6 weeks for a maximum of 6 cycles. Patients were assessed for toxicity at the time of infusion and sequentially thereafter. Response was evaluated clinically and radiologically at least every 6 weeks. RESULTS: Treatment was well tolerated. Dose reductions were required at least once in 18 patients, treatment delays were necessary at least once in 33 patients. Grade 3-4 leukopenia occurred in 6 patients (12 events), grade 3-4 thrombocytopenia in 10 patients (25 events) and grade 3-4 liver enzymes elevations in 18 patients (31 events). Higher fluosol dosages did not produce increases in toxicity or responses. Response or stabilization was seen in 57% (38% were stabilizations) of the patients who entered the trial with progressive disease. The median time to progression was 45 weeks, and median survival was 66 weeks for patients who had response or stabilization. For patients with glioblastoma response/stabilization was seen in 45% with a mean duration of 24 weeks, for patients with anaplastic astrocytoma response/stabilization was seen in 68% with a mean duration of 50 weeks. CONCLUSION: This treatment regimen is well tolerated. Our results suggest fluosol may enhance the effectiveness of BCNU for the treatment of recurrent malignant gliomas. Future studies will be performed using fluosol at the dose of 400 ml/m2.

Adolescent↗
PubMed1997

Plasma RRR-alpha-tocopherol concentrations are lower in smokers than in non-smokers after ingestion of a similar oral load of this antioxidant vitamin.

1. Using deuterium-labelled alpha-tocopherol (vitamin E), the plasma kinetics of alpha-tocopherol derived from supplemental RRR-alpha-tocopherol and RRR-alpha-tocopheryl acetate were determined in asymptomatic individuals who smoke and, for comparison, in a group of healthy non-smokers. 2. Venous blood samples were withdrawn 6, 12 and 27 h after the oral administration of a gelatin capsule containing an equimolar mixture of RRR-alpha-tocopheraol and RRR-alpha-tocopheryl acetate. Plasma concentrations of endogenous and administered forms of alpha-tocopherol were determined by a combination of HPLC and GC-MS. 3. Both the free phenol and the acetate ester concentrations of alpha-tocopherol were lower in smokers than in non-smokers: 0.99 versus 1.60 (P < 0.05) and 0.66 versus 1.49 (P < 0.05) mumol/mmol cholesterol for RRR-alpha-tocopherol and RRR-alpha-tocopheryl acetate respectively. The highest concentation of alpha-tocopherol derived from administered RRR-alpha-tocopherol and its acetate ester were observed in plasma at 12 h (compared with 6-h and 27-h measurements) in most subjects. 4. Although the two forms of alpha-tocopherol were administered in equal doses, plasma from smokers contained significantly higher concentrations of RRR-alpha-tocopherol derived from the free phenol form than from the acetate form (0.99 versus 0.66 mumol/mmol cholesterol, P < 0.05, 12 h). Non-smokers did not exhibit preferential uptake of either form of vitamin E. 5. These results suggest that individuals who smoke have either a reduced ability to absorb alpha-tocopherol, particularly when it is presented as the acetate ester, or increased clearance of newly absorbed alpha-tocopherol compared with non-smokers.

Administration, Oral↗
PubMed1997

The use of the bladder neck support prosthesis in combined genuine stress incontinence and detrusor instability.

The Bladder Neck Support Prosthesis (BNSP) was used in 21 women with combined genuine stress incontinence (GSI) and detrusor instability (DI). Outcomes included frequency volume charts, pad tests, voiding cystometry and quality of life scores, up to the sixth month. Of the 21 recruits, 5 never wore the BNSP home, leaving 16 participants. A further 2 did not reach week 4 because of poor efficacy or inability to fit the device. In the 14 who reached week 4, the median number of leaks/day declined from 4.3 to 1.0 (p = 0.002). Median pad test loss fell from 53 to 7 mL (p = 0.012). Cystometry showed an increase in maximum bladder capacity (p < 0.05) and a modest reduction in severity of detrusor instability, with no evidence of outflow obstruction. Three further women discontinued because of poor efficacy (2) or a poorly fitting device (1), leaving 11 of 16 participants (69%) at week 8, when median pad test loss fell to 2 mL. The BNSP is a useful option in patients with the unfortunate combination of an unstable bladder and an incompetent urethra, but requires careful fitting and attention to detail.

Aged↗