PubMed Health⌕ Search

Biomedical subjects

P Bevan

Publications and source records attributed to P Bevan.

At least 19 recordsLinked to original sources
PubMed2004

Ensembl 2004.

The Ensembl (http://www.ensembl.org/) database project provides a bioinformatics framework to organize biology around the sequences of large genomes. It is a comprehensive and integrated source of annotation of large genome sequences, available via interactive website, web services or flat files. As well as being one of the leading sources of genome annotation, Ensembl is an open source software engineering project to develop a portable system able to handle very large genomes and associated requirements. The facilities of the system range from sequence analysis to data storage and visualization and installations exist around the world both in companies and at academic sites. With a total of nine genome sequences available from Ensembl and more genomes to follow, recent developments have focused mainly on closer integration between genomes and external data.

Animals↗
PubMed2003

Ensembl 2002: accommodating comparative genomics.

The Ensembl (http://www.ensembl.org/) database project provides a bioinformatics framework to organise biology around the sequences of large genomes. It is a comprehensive source of stable automatic annotation of human, mouse and other genome sequences, available as either an interactive web site or as flat files. Ensembl also integrates manually annotated gene structures from external sources where available. As well as being one of the leading sources of genome annotation, Ensembl is an open source software engineering project to develop a portable system able to handle very large genomes and associated requirements. These range from sequence analysis to data storage and visualisation and installations exist around the world in both companies and at academic sites. With both human and mouse genome sequences available and more vertebrate sequences to follow, many of the recent developments in Ensembl have focusing on developing automatic comparative genome analysis and visualisation.

Animals↗
PubMed2001

Insulin signalling.

Explore the source record for details and available documents.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Phase I trial of XR9576 in healthy volunteers demonstrates modulation of P-glycoprotein in CD56+ lymphocytes after oral and intravenous administration.

XR9576 is a novel inhibitor of P-glycoprotein (P-gp) that has been shown to reverse P-gp-dependent multidrug-resistance in tumor cell lines and tumor-bearing animals. Here we report the first i.v. and p.o. administration to healthy volunteers of XR9576 in dose-escalating studies with the aim of investigating its effects on safety, its pharmacokinetics, and a surrogate marker of efficacy. XR9576 was administered as a single dose-upward titration of 0.1, 0.2, 0.5, 1.0, and 2 mg/kg XR9576 i.v. or 50, 100, 200, 500, and 750 mg/volunteer p.o. The surrogate marker for in vivo efficacy examined the accumulation of the P-gp substrate Rhodamine-123 (Rh-123) in P-gp-expressing CD56+ lymphocytes by flow cytometry. Addition of Rh-123 to blood samples from subjects given XR9576 or a placebo demonstrated drug-dependent modulation of P-gp activity. Even at the lowest doses, significant effects were observed on Rh-123 accumulation in CD56+ cells. Maximal effects were seen during the i.v. infusion or 4-6 h after oral administration. As the dose was increased, a concomitant rise in the level and duration of P-gp blockade was observed. A dose of 2.0 mg/kg i.v. and > or = 200 mg/volunteer p.o. gave approximately 100% inhibition of P-gp for in excess of 24 h. All doses of XR9576 were well tolerated. Inhibition increased with XR9576 plasma concentration, and maximal activity was achieved at 150-200 ng/ml XR9576. In conclusion, XR9576 has demonstrated sustained inhibition of P-gp after i.v. and oral administration and, supported by the elimination half-life of about 24 h, XR9576 is being taken into Phase II as a once-daily agent.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Reversal of P-glycoprotein-mediated multidrug resistance by XR9051, a novel diketopiperazine derivative.

XR9051 (N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phe nyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-pipera zinylidene) methylbenzamide) was identified as a potent modulator of P-glycoprotein-mediated multidrug resistance (MDR) following a synthetic chemistry programme based on a natural product lead compound. The activity of XR9051 was determined using a panel of human and murine drug-resistant cell lines (H69/LX4, 2780AD, EMT6/AR 1.0, MC26 and P388/DX Johnson). XR9051 was able to reverse resistance to a variety of cytotoxic drugs, including doxorubicin, etoposide and vincristine, which are associated with classical MDR. At a concentration of 0.3-0.5 microM, XR9051 was able to fully sensitize resistant cells to cytotoxics, whereas little or no effect was observed on the corresponding parental cell lines. No effect of XR9051 was observed on the response of cells to non-MDR cytotoxics such as methotrexate and 5-fluorouracil. XR9051 was consistently more potent than cyclosporin A (CsA) and verapamil (Vpm) in all assays used. XR9051 inhibited the efflux of [3H]daunorubicin from preloaded cells and, unlike CsA and Vpm, remained active for several hours after removal of resistance-modifying agent. In photoaffinity labelling experiments employing [3H]azidopine, XR9051 was able to displace binding to P-glycoprotein. In binding studies using [3H]vinblastine, XR9051 was shown to be a potent inhibitor of the binding of the cytotoxic to P-glycoprotein (EC50 = 1.4 +/- 0.5 nM). Taken together, the results indicate that XR9051 reverses the MDR phenotype through direct interaction with P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Novel low-molecular-weight inhibitor of PAI-1 (XR5118) promotes endogenous fibrinolysis and reduces postthrombolysis thrombus growth in rabbits.

BACKGROUND: Elevated levels of plasminogen activator inhibitor 1 (PAI-1) have been associated with the occurrence of thrombotic disease, and inhibition of PAI-1 activity in vivo resulted in enhanced thrombolysis and a reduction in reocclusion. Besides monoclonal antibodies and peptides, no suitable agents that are able to block PAI-1 activity are available to date. The present study was designed to test the interaction between a nonantibody, nonpeptide, diketopiperazine-based inhibitor of PAI-1, XR5118, and PAI-1 and to assess the effect of XR5118 on PAI-1 activity in vitro and on in vivo thrombolysis and thrombus growth in an experimental thrombosis model in rabbits. METHODS AND RESULTS: The binding site of XR5118 on the PAI-1 molecule was studied by competitive binding experiments with mapped anti-PAI-1 monoclonal antibodies by use of surface plasmon resonance experiments. XR5118 selectively and competitively inhibited binding of the PAl-1-inhibiting monoclonal antibody CLB-2C8, indicating that binding of XR5118 to PAI-1 takes place at the area between amino acids 110 and 145 of the PAI-1 molecule, which is known to be involved with the binding of PAI-1 to tissue plasminogen activator (TPA). Incubation of plasma or platelet releasate with XR5118 resulted in a dose-dependent inhibition of PAI-1 activity. Systemic infusion of XR5118 induced a significant reduction in plasma PAI-1 activity levels from 23.7+/-4.9 to 10.9+/-3.4 IU/mL. Administration of XR5118 resulted in a significant, twofold increase in endogenous thrombolysis compared with the control. Thrombus growth in rabbits receiving both XR5118 and rTPA was significantly attenuated compared with rabbits receiving rTPA alone (13.5+/-2.7% versus 19.9+/-3.8%, respectively). CONCLUSIONS: XR5118 binds to PAI-1 and reduces plasma PAI-1 activity levels. Furthermore, XR5118 promotes endogenous thrombolysis and inhibits thrombus accretion and is the first nonpeptide compound with significant anti-PAI-1 activity in vivo in these models.

Animals↗
PubMed1997

Regulation of neuronal and recombinant GABA(A) receptor ion channels by xenovulene A, a natural product isolated from Acremonium strictum.

Xenovulene A (XR368) is a natural product exhibiting little structural resemblance with classical benzodiazepines yet is able to displace high-affinity ligand binding to the benzodiazepine site of the gamma-aminobutyric acid (GABA)A receptor. We have characterized this compound and an associated congener (XR7009) by use of radioligand binding and electrophysiological methodologies with native neurons and the Xenopus oocyte expression system. Xenovulene A, and the more potent XR7009, inhibited [3H]flunitrazepam binding to rat forebrain with Ki values of 7 and 192 nM, and 1.7 and 42 nM, respectively, each site accounting for approximately 50% of the total specific binding. In cerebellar and spinal cord membranes, these ligands identified only single binding sites. These ligands demonstrated no intrinsic agonist activity at recombinant GABA(A) receptors comprising alpha1beta1gamma2S subunits expressed in Xenopus oocytes, yet at 1 microM both significantly potentiated the GABA-induced response and reduced the GABA EC50 from 10.9 (control) to 5.1 (Xenovulene A) or 2.7 microM (XR7009). The rank potency order for enhancement of the 10 microM GABA response is: XR7009 (EC50, 0.02 microM) > diazepam (0.03) > Xenovulene A (0.05) > flurazepam (0.17). The activity of XR368 and XR7009 was reduced by the benzodiazepine antagonist, flumazenil, and absent in receptors devoid of the gamma2 subunit. These agents exhibited receptor subtype selectivity because alpha3beta1gamma2S receptors were less sensitive to these compounds relative to alpha1 subunit-containing receptors, whereas alpha6beta1gamma2S receptors were completely insensitive. Potentiation of the response to GABA on native GABA(A) receptors in cortical neurons substantiates the profile of the novel structures of Xenovulene A and XR7009 as specific benzodiazepine agonists.

Acremonium↗
PubMed1996

Evaluation of a low molecular weight modulator of human plasminogen activator inhibitor-1 activity.

A critical component in the regulation of thrombus formation and clearance is the balance between tissue plasminogen activator (tPA) and plasminogen activator inhibitor type-1 (PAI-1). An increase in the plasma concentration of PAI-1 has been proposed as a risk factor in thrombotic disease. Inhibition of PAI-1 activity may have utility in the treatment of thromboembolic disease. We report here the evaluation of three diketopiperazine-based low molecular weight inhibitors of PAI-1 activity (XR334, XR1853 and XR5082). In vitro these compounds reversed the inhibitory effects of PAI-1 against both tPA and urokinase (UK) (IC50: 5 to 80 muM). In contrast, other serpin-serine protease interactions, including alpha 1-antitrypsin-trypsin, alpha 2-antiplasmin- plasmin and antithrombin-thrombin, were not affected, neither did these inhibitors affect global tests of haemostasis. In the light of this promising in vitro profile these compounds were evaluated in a standard radioisotopic assay of clot lysis in whole rat blood following intravenous administration. In this assay these compounds dose-dependently enhanced fibrinolysis ex vivo. After intravenous bolus administration XR334, XR1853 and XR5082 at 5 mg/kg increased clot lysis by 32.0 +/- 5.1% SEM (n = 25, p < 0.01), 36.7 +/- 3.5% SEM (n = 36, p < 0.01) and 60.0 +/- 2.8% SEM (n = 17, p < 0.01) respectively compared to vehicle. Intravenous infusion of these compounds (1 mg/kg/min for 20 min) significantly prolonged (approximately twofold) the time to blood vessel occlusion in the rat electrically-stimulated carotid artery thrombosis model. Thus, these low molecular weight inhibitors of PAI-1 activity enhanced fibrinolysis ex vivo and protected against thrombus formation in the rat.

Animals↗
PubMed1995

Identifying small-molecule lead compounds: the screening approach to drug discovery.

A number of new technologies that enable high-throughput, cost-effective screening of potential drug candidates have been developed in recent years. Such compounds may be derived from the large proprietary collections held by pharmaceutical companies, from new synthetic approaches such as combinatorial chemistry, or from natural sources. The latter remain a major source of new chemicals: many are already used in human treatment and many others are currently undergoing evaluation as the potential medicines of the future.

Chemistry, Pharmaceutical↗
PubMed1988

Evidence that the novel antihypertensive agent, flesinoxan, causes differential sympathoinhibition and also increases vagal tone by a central action.

The effects of flesinoxan were studied on thoracic preganglionic, splanchnic and renal sympathetic nerve activity, carotid sinus nerve activity, blood pressure and heart rate in anaesthetised cats. In some experiments femoral or renal arterial conductance was also recorded. Flesinoxan (3-300 micrograms kg-1) caused a dose-related fall in blood pressure and heart rate and also caused sympathoinhibition. This fall in blood pressure was not associated with changes in femoral arterial conductance but was with a large increase in renal arterial conductance. In this respect flesinoxan had a greater sympathoinhibitory action on the renal nerve compared with the other sympathetic outflows. The bradycardia was unaffected by the 5-HT3 antagonist, MDL 72222, but was reversed by atropine and was abolished in bi-vagotomised cats. Flesinoxan also caused sympathoinhibition in bi-vagotomised cats and decreased carotid sinus nerve activity and blood pressure. It is concluded that flesinoxan acts centrally to cause sympathoinhibition and an increase in vagal tone.

Animals↗
PubMed1988

Flesinoxan lowers blood pressure and heart rate in cats via 5-HT1A receptors.

Flesinoxan, a new phenylpiperazine derivative has been shown to lower blood pressure in different species after both oral and i.v. administration. The present study shows that the hypotensive potency of flesinoxan in anaesthetised cats increased 35 times after administration via the vertebral arteries compared to i.v. administration. These results, which were confirmed by intracisternal administration, point strongly to a central site of action. Haemodynamic studies indicated that the blood pressure reduction in anaesthetised cats was mainly due to a reduction in the total peripheral resistance and only to some extent to a reduced cardiac output. Flesinoxan seems not to affect sympathetic function by a peripheral mechanism. Its cardiovascular profile can be explained by a centrally mediated reduction of sympathetic tone and increase in vagal tone. Receptor binding studies indicated that flesinoxan is a very potent and selective 5-HT1A ligand. The decreases in blood pressure and heart rate induced by centrally administered flesinoxan and 8-OH-DPAT, could be antagonized effectively by the putative 5-HT1A antagonist pindolol. This suggests a relationship between blood pressure reduction and central 5-HT1A receptors.

Animals↗
PubMed1988

An in vitro mature spinal cord preparation from the rat.

The preparation of an isolated hemisected spinal cord preparation, maintained in vitro, from mature (180-300 g body weight) rats is described. Sacral and coccygeal segments (S2-Co1) gave consistent ventral root reflexes (DR-VRP) from electrical stimulation of dorsal roots. The mean latency and amplitude of the fastest component in the ventral root reflex, at 25 degrees C, were 1.6 msec +/- 0.4 SE mean and 8.2 mV +/- 0.9 SE mean, respectively (28 preparations). This component was resistant to the NMDA antagonist, 2-amino-5-phosphonopentanoate (AP5) but was depressed markedly by kynurenate. A slow component of the ventral root reflex, which was sensitive to AP5 was enhanced and spontaneous AP5-sensitive synaptic potentials sensitive to AP5 appeared in the absence of magnesium ions. The excitant amino acids L-aspartate, L-glutamate, N-methyl-D-aspartate (NMDA), kainate and quisqualate produced dose-dependent depolarizing responses in the ventral roots. The relative depolarizing potencies +/- SE mean (N) of NMDA, kainate and quisqualate, relative to L-glutamate = 1, were 96 +/- 30 (6), 234 +/- 57 (6) and 145 +/- 40 (5), respectively. These properties, apart from reduced latency of synaptic responses, are similar to those described previously for preparations from immature animals. However, it will be easier with the mature preparation to selective activate high and low threshold primary afferents.

Amino Acids↗
PubMed1984

[3H]oxotremorine-M binding to membranes prepared from rat brain and heart: evidence for subtypes of muscarinic receptors.

[3H]Oxotremorine-M has been used as a ligand to label muscarinic binding sites on membranes prepared from rat fore-brain and heart. In rat brain membranes, two binding sites could be identified: a high affinity low capacity site and a low affinity high capacity site. In contrast, only a high affinity site could be labelled in heart membranes. The potency order of agonists for the high affinity site in brain membranes and heart membranes was the same, suggesting that these binding sites represent the same subtype of muscarinic receptors. However, the affinity of pirenzepine for the brain high affinity site was higher than that for the heart high affinity site suggesting that these sites may represent different receptor populations. The potency order of agonists for the high affinity and low affinity sites in brain membranes were significantly different suggesting that these binding sites represent pharmacologically distinct binding sites. GTP abolished the high affinity sites in heart and brain membranes, but the low affinity site in brain membranes appeared unaffected. These results are consistent with the hypothesis proposing subtypes of muscarinic receptors.

Animals↗
PubMed1984

Effect of muscarinic ligands on the electrical activity recorded from the hippocampus: a quantitative approach.

The electrical activity of the hippocampus was recorded from the CA 1 region in rats anaesthetized with halothane and the effects of compounds assessed following their intravenous injection. Quantification of the effects was achieved following on-line fast Fourier transformation of the signal. The electrical activity recorded from the hippocampus of the halothane-anaesthetized rat demonstrated identical characteristics to that recorded from the freely-moving animal. Three types of activity could be distinguished: rhythmical slow wave activity (RSA or theta); large amplitude slow wave activity (LIA); and small amplitude fast wave activity. Muscarinic agonists induced RSA with a consequent reduction in power. The effects were dose-dependent and were reversibly antagonized by scopolamine, but not methyl-scopolamine, indicating that the effects are mediated centrally by muscarinic receptors. The results show that, in halothane anaesthetized rats, a muscarinic RSA occurs which is unrelated to movement or behavioural arousal.

Amphetamine↗
PubMed1983

beta-RTX. A receptor-active protein from Russell's viper (Vipera russelli russelli) venom.

A single chain polypeptide, termed beta-RTX, with an apparent Mr = 9600 has been isolated from the venom of Vipera russelli russelli. It was purified by cation exchange chromatography, followed by preparative isoelectric focusing and chromatofocusing. Purity was confirmed by gel filtration, high performance liquid chromatography, gel electrophoresis, and analytical ultracentrifugation. Amino acid analysis revealed the presence of eight half-cystines, one being located at the NH2 terminus, which are linked to form four intramolecular disulfide bridges. Chromatofocusing revealed some microheterogeneity yielding three isoforms with pI values of 9.3, 9.37, and 9.48, respectively. In its native configuration, beta-RTX was not susceptible to tryptic degradation but was readily digested after reduction and alkylation. beta-RTX possesses weak phospholipase A2 activity and competes with the binding of monoamines and opiate ligands to their respective receptors. No binding to histamine, gamma-aminobutyric acid, benzodiazepine, or muscarinic receptors was observed. In vivo, whereas 100 micrograms/kg intravenous beta-RTX seemed to be without apparent effects in the rat, 10 ng/kg beta-RTX injected intracerebroventricularly caused marked sedation, with full recovery within 3 h.

Animals↗
PubMed1983

Repeated apomorphine treatment causes behavioural supersensitivity and dopamine D2 receptor hyposensitivity.

This study reports the changes in the behavioural responsiveness of rats in the "Ungerstedt Model' following repeated injections of apomorphine. The changes in striatal [3H]haloperidol binding coincident with the behavioural responses are also estimated. Following unilateral lesions of the substantia nigra, the number of [3H]haloperidol binding sites in the ipsilateral striatum increase, and this effect correlates with the behavioural effect following a single apomorphine injection. Repeated apomorphine treatment, however, results in a decrease of neuroleptic binding sites in the ipsilateral and contralateral striatum accompanied by increased behavioural responses. Thus repeated apomorphine treatment discriminates the receptor mechanisms involved in the behavioural response from those receptors labelled by neuroleptics.

Animals↗