Abstract:
BACKGROUND AND PURPOSE:Pharmacokinetic/pharmacodynamic (PK/PD) models are necessary to relate the degree of drug exposure in vivo to target blockade and pharmacological efficacy. This manuscript describes a murine agonist-induced CXCR3 receptor internalization assay and demonstrates its utility for PK/PD analyses. EXPERIMENTAL APPROACH:Activated murine DO11.10 cells were incubated with agonist in the presence or absence of a CXCR3 antagonist and changes in surface CXCR3 expression were detected by flow cytometry. For PK/PD analysis, mice were dosed with a small molecule CXCR3 antagonist, NBI-74330, (100 mg kg(-1)) orally or subcutaneously and plasma samples taken at specified timepoints for the CXCR3 internalization assay. KEY RESULTS:Surface CXCR3 expression was specifically decreased in response to CXCL9, CXCL10 and CXCL11. CXCL11 was the most potent CXCR3 agonist in buffer (pA50=9.23+/-0.26) and the pA50 for CXCL11 was unaltered in murine plasma (pA50=9.17+/-0.15). The affinity of a small molecule CXCR3 antagonist, NBI-74330, was obtained in the absence or presence of plasma (buffer pA2 value: 7.84+/-0.14; plasma pKB) value 6.36+/-0.01). Administration of NBI-74330 to mice resulted in the formation of an N-oxide metabolite, also an antagonist of CXCR3. Both antagonists were detectable up to 7 h post oral dose and 24 h post subcutaneous dose. Measurement of CXCR3 internalization demonstrated significant antagonism of this response ex vivo, 24 h following subcutaneous administration of NBI-74330. CONCLUSIONS AND IMPLICATIONS:The CXCR3 receptor internalization assay provides a robust method for determining agonist potency orders, antagonist affinity estimates and PK/PD analyses, which discriminate between dosing regimens for the CXCR3 antagonist NBI-74330.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Jopling LA,Watt GF,Fisher S,Birch H,Coggon S,Christie MIdoi
10.1038/sj.bjp.0707519subject
Has Abstractpub_date
2007-12-01 00:00:00pages
1260-71issue
8eissn
0007-1188issn
1476-5381pii
0707519journal_volume
152pub_type
杂志文章abstract:BACKGROUND AND PURPOSE:Cigarette smoke is a major cause for chronic obstructive pulmonary disease (COPD). Andrographolide is an active biomolecule isolated from the plant Andrographis paniculata. Andrographolide has been shown to activate nuclear factor erythroid-2-related factor 2 (Nrf2), a redox-sensitive antioxidant...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.12054
更新日期:2013-04-01 00:00:00
abstract::1 Twenty-two compounds classified as antidepressants, metabolites of antidepressants or putative antidepressants were assayed for their ability to antagonize the binding of (-)-[3H]-quinuclidinyl benzilate to muscarinic receptors in homogenates of human caudate nucleus. 2 Sixteen of these compounds were assayed for th...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:
更新日期:1983-01-01 00:00:00
abstract::1. alpha 1-Adrenoceptor subtypes in rabbit thoracic aorta have been examined in binding and functional experiments. 2. [3H]-prazosin bound to two distinct populations of alpha 1-adrenoceptors (pKD,high = 9.94, Rhigh = 79.2 fmol mg-1 protein; pKD,low = 8.59, Rlow = 215 fmol mg-1 protein). Pretreatment with chloroethylc...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1993.tb13507.x
更新日期:1993-04-01 00:00:00
abstract::1. The distribution and some pharmacological properties of centrally located dextromethorphan high-affinity binding sites were investigated by in vitro autoradiography. 2. Sodium chloride (50 mM) induced a 7 to 12 fold increase in dextromethorphan binding to rat brain in all areas tested. The effect of sodium was conc...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0701043
更新日期:1997-04-01 00:00:00
abstract::1. Aggressive behaviour was elicited in rats that had been deprived of food for 20 h daily (starved), by chronic administration of Cannabis sativa extract or (-)-Delta(9)-trans-tetrahydrocannabinol.2. The influence of intraperitoneal (i.p.) or oral glucose administration, cold environment, acidosis, and corn, and prot...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1972.tb07317.x
更新日期:1972-04-01 00:00:00
abstract::1. The experiment investigated the effects of psychotropic drugs on enzymes in vitro.2. Chlorpromazine inhibits mitochondrial malate dehydrogenase in concentrations of 1.4x10(-4)M and above. No effect was observed below this concentration.3. A sharp inflection in the [unk]/drug plot was also seen with chlorpromazine (...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1969.tb10582.x
更新日期:1969-10-01 00:00:00
abstract::1. Human mast cell tryptase appears to display considerable variation in activating proteinase-activated receptor 2 (PAR(2)). We found tryptase to be an inefficient activator of wild-type rat-PAR(2) (wt-rPAR(2)) and therefore decided to explore the factors that may influence tryptase activation of PAR(2). 2. Using a 2...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0704303
更新日期:2001-10-01 00:00:00
abstract::1. The oral sedative potencies of cannabis herb, crude ethanolic and petroleum-ether fractions, were assayed against delta'-trans-tetrahydrocannabinol (THC) administered orally to mice, by measuring spontaneous motor activity over 30 min periods, at selected times, up to 6 h. 2. The THC contents of the extracts were d...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1981.tb09145.x
更新日期:1981-04-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Muscarinic toxins (MTs) are snake venom peptides named for their ability to interfere with ligand binding to muscarinic acetylcholine receptors (mAChRs). Recent data infer that these toxins may have other G-protein-coupled receptor targets than the mAChRs. The purpose of this study was to systema...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2011.01468.x
更新日期:2011-09-01 00:00:00
abstract::1. It has recently been shown that both alpha(1)- and alpha(2)-adrenoceptors mediate vasoconstriction in the canine external carotid circulation. The present study set out to identify the specific subtypes (alpha(1A), alpha(1B) and alpha(1D) as well as alpha(2A), alpha(2B) and alpha(2C)) mediating the above response. ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0703915
更新日期:2001-03-01 00:00:00
abstract::1 The appearance of pancreatic muscarinic receptors during development has been measured by use of the specific ligand [3H]-quinuclidinyl benzilate ([3H]-QNB). 2 QNB binding sites are present in foetal pancreas; their maximal concentration is attained at the age of 30 days and a significant decrease is observed in one...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1981.tb10428.x
更新日期:1981-06-01 00:00:00
abstract::1. We have taken advantage of our recent development of highly potent and specific phosphinic inhibitors of endopeptidase 3.4.24.15 to examine the putative contribution of the enzyme in the secretion of A beta by HK293 transfected cells overexpressing the wild type and the Swedish (Sw) double mutated form of beta APP7...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0701151
更新日期:1997-06-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor agonists display a promising analgesic profile in preclinical studies. However, supraspinal N/OFQ produced hyperalgesia in rodents and such effects have not been addressed in primates. Thus, the aim of this study was to investigate the effects...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.13124
更新日期:2015-07-01 00:00:00
abstract::1 We have examined the effect of the histone deacetylase inhibitors apicidin, trichostatin A (TSA) and n-butyrate on the histone acetylation and the differentiation of human eosinophilic leukemia HL-60 clone 15 cells into eosinophils. 2 Viability of the cells incubated with apicidin (100 nm), TSA (30 nm) or n-butyrate...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0705869
更新日期:2004-07-01 00:00:00
abstract::Chronic heart failure (HF) is characterized by left ventricular (LV) structural remodeling, impaired function, increased circulating noradrenaline (NA) levels and impaired responsiveness of the myocardial beta-adrenoceptor (betaAR)-adenylyl cyclase (AC) system. In failing hearts, inhibition of the sodium/proton-exchan...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0706714
更新日期:2006-05-01 00:00:00
abstract::Substance P and substance K (neurokinin A) (dose range: 0.08-80 nmol kg-1) were tested for their effects on gastrointestinal propulsion in the rat. The peptides were given by intraperitoneal injection concurrently with the intragastric administration of a test meal containing charcoal and 51Cr. Examination 3 min after...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1985.tb09462.x
更新日期:1985-09-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Although trace amines (TAs) are historically considered 'false neurotransmitters' on the basis of their ability to induce catecholamine release, there is evidence that they directly affect neuronal activity via TA receptors, ligand-gated receptor channels and/or sigma receptors. Here, we have inv...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2010.00792.x
更新日期:2010-07-01 00:00:00
abstract::1 The effects of indomethacin and eicosa-5,8,11,14-tetraynoic acid (ETYA) on the contractile response of the transmurally stimulated rabbit portal vein were studied in vitro.2 When the veins were stimulated for 240 pulses at 1 and 2 Hz, the responses were potentiated by indomethacin and ETYA. However, responses to 4 a...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1974.tb09687.x
更新日期:1974-09-01 00:00:00
abstract::1. We have studied whether a nucleotide receptor mediates the effects of extracellular ATP and UTP on phosphatidylcholine metabolism in rat cultured glomerular mesangial cells. 2. ATP and UTP stimulated a biphasic 1,2-diacylglycerol (DAG) formation in [3H]-arachidonic acid-labelled mesangial cells. In contrast, in cel...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1993.tb13890.x
更新日期:1993-10-01 00:00:00
abstract::1. Therapeutic doses of colistin sulphomethate sodium B.P. (Colomycin), pento-N sulphomethylpolymyxin B sodium (Thiosporin) and ampicillin B.P. (Penbritin) as well as normal saline have been given to volunteers with normal kidney function.2. A blind crossover technique was used and the effects of the compounds on bloo...
journal_title:British journal of pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1111/j.1476-5381.1969.tb09545.x
更新日期:1969-09-01 00:00:00
abstract::1,2,3,4-Tetrahydro-9-aminoacridine (THA) has an inhibitory effect on the activity of acetylcholinesterase which has led to its use in the treatment of Alzheimer's disease. Other actions of THA include the inhibition of voltage-dependent ion channels. In this paper we describe the effect of THA on the depolarization-in...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1988.tb11615.x
更新日期:1988-08-01 00:00:00
abstract:BACKGROUND AND PURPOSE:The two longest C-termini of the purinergic P2X receptors occur in the P2X2 and P2X7 receptors and are thought to interact with multiple cytoplasmic proteins, among which are members of the cytoskeleton, including microtubules. In this work we asked whether disrupting the microtubule cytoskeleton...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2011.01254.x
更新日期:2011-07-01 00:00:00
abstract::1 Post-tetanic potentiation (p.t.p.) of the compound action potential in the presence of hexamethonium was observed in the isolated stellate ganglion of the hamster using extracellular postganglionic recordings. 2 The magnitude of the p.t.p. was small (less than a 20% increase) in the control solution, but increased a...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1980.tb07897.x
更新日期:1980-06-01 00:00:00
abstract:BACKGROUND AND PURPOSE:The aim of this study was to identify the actions of H(2)S on ion transport across rat distal colon. EXPERIMENTAL APPROACH:Changes in short-circuit current (Isc) induced by the H(2)S-donor, NaHS, were measured in Ussing chambers. Cytosolic Ca(2+) concentration was evaluated using fura-2. KEY RE...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2009.00385.x
更新日期:2009-11-01 00:00:00
abstract::1 The effects of alpha- and beta-adrenoceptor stimulants on the histamine-forming capacity (HFC) of human isolated leucocytes have been studied, in vitro.2 It was confirmed that antigen significantly stimulates the HFC of human leucocytes.3 beta-Adrenoceptor stimulants, such as isoprenaline and salbutamol (10(-6)-10(-...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1974.tb09702.x
更新日期:1974-10-01 00:00:00
abstract::1. Cold storage (2 degrees C) treatment progressively reduced noradrenaline uptake by the taenia caecum of the guinea-pig. After 15 days of cold treatment, [(3)H]-noradrenaline uptake by tissue was reduced to about 10% of control. On the other hand, prolonged cold storage failed to decrease [(3)H]-adenosine uptake by ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1973.tb08539.x
更新日期:1973-12-01 00:00:00
abstract::1 Adenosine, adenosine monophosphate and adenosine triphosphate (ATP) depressed the firing rate of neurones in the rat cerebral cortex when applied by microinontophoresis. 2 4-Aminopyridine, also applied iontophoretically blocked the depressant effects of the purines, without affecting responses to gamma-aminobutyric ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1980.tb08720.x
更新日期:1980-11-01 00:00:00
abstract::1. ATP, UTP, ADP and ADP-beta-S elicited Ca2+ -signals in cultured aortic smooth muscle cells although ADP, UDP and ADP-beta-S gave approximately 40% of the maximal response seen with ATP and UTP. Adenosine, AMP or alpha,beta-methylene-ATP had no effect. These responses were attributed to P2Y2/4 and P2Y1 receptors, wh...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0702470
更新日期:1999-04-01 00:00:00
abstract::Adenosine enhanced histamine release and prolonged the adenosine 3':5'-cyclic monophosphate (cyclic AMP) response in purified rat peritoneal mast cells following immunological challenge. The effect on the cyclic AMP response, which was blocked by 8-phenyltheophylline, probably results from an interaction with A2-purin...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1985.tb08823.x
更新日期:1985-05-01 00:00:00
abstract::1. Intraplantar administration of the nitric oxide (NO) donor, sodium nitroprusside (SNP), induces hyperaemia in the rat paw skin, which is in part due to release of calcitonin gene-related peptide (CGRP) from afferent nerve fibres. The present study examined whether prostaglandins or other inflammatory mediators part...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1995.tb15081.x
更新日期:1995-11-01 00:00:00