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Unexpectedly high affinity of a novel histamine H3receptor antagonist, GSK239512,in vivoin human brain, determined using PET
2014
British Journal of Pharmacology
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BACKGROUND AND PURPOSE This study aimed to investigate the relationship between the plasma concentration (PK) of the novel histamine H3 receptor antagonist, GSK239512, and the brain occupancy of H3 receptors ...
CONCLUSIONS AND IMPLICATIONS The affinity of GSK239512 for brain H3 receptors in humans in vivo is much higher than that expected from studies in vitro, and higher than that observed in PET studies in ...
Sharon Ashworth, Alienor Berges, Eugenii Rabiner, Robert Comley, Robert Lai, Rebecca Boardley, Graham Searle, Roger Gunn, Marc Laruelle and Vincent Cunningham were all GSK employees at the time the study ...
doi:10.1111/bph.12505
pmid:24670146
pmcid:PMC3952801
fatcat:fzogiu5pyve23iskkvrmi3kx2q
Population pharmacokinetics of nalmefene in healthy subjects and its relation to μ-opioid receptor occupancy
2016
British Journal of Clinical Pharmacology
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AIMS The aims of this study were to develop a population pharmacokinetic (PK) model to describe the PK of nalmefene in healthy subjects and to relate the exposure of nalmefene to the μ-opioid receptor ...
occupancy by simulations in the target population. ...
Lundbeck A/S for this analysis and there are no other relationships or activities that could appear to have influenced the submitted work. ...
doi:10.1111/bcp.12805
pmid:26483076
pmcid:PMC4833148
fatcat:ruojmdzkrvgwhgek2xky2bsnxm
An in vivo Positron Emission Tomography Study of Adenosine 2A Receptor Occupancy by Preladenant using 11C-SCH442416 in Healthy Subjects
2014
Journal of Diagnostic Imaging in Therapy
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In this study we demonstrated the importance of PET imaging for establishing PK-PD relationships and utilizing this tool in confirming proof-of-target and dose guidance for Phase 2/3 clinical trials. ...
A 5 mg dose, administered BID, was estimated to provide ≥50% receptor occupancy in approximately 75% of the population for the majority of waking hours (12 hours/day). ...
Cunningham for help with the imaging data analysis, and Amol Tendolkar for help with PK-PD modeling. Drs. ...
doi:10.17229/jdit.2014-0712-002
fatcat:dyw5s4nqgjhmpkvi6xpxylteem
Therapeutic window of dopamine D2/3 receptor occupancy to treat psychosis in Alzheimer's disease
2017
Brain
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Non-linear mixed effects modelling was used to describe pharmacokinetic-occupancy curves in caudate, putamen and thalamus. ...
; NLME = Non-linear mixed effects modelling; Caverage = Average steady state exposure across the dosage interval (24 hours); EPS = Extrapyramidal side effects; PK = Pharmacokinetic. 3 Abstract Antipsychotic ...
., 2004) , who modelled the non-linear occupancy curve for [ 18 F]desmethoxyfallypride, and whose estimates for amisulpride blood concentration required to achieve 60% occupancy in caudate (119ng/ml) and ...
doi:10.1093/brain/aww359
pmid:28334978
fatcat:sv6agjdcpjdp3b3gfolprd6pdi
Differentiated effects of the multimodal antidepressant vortioxetine on sleep architecture: Part 1, a pharmacokinetic/pharmacodynamic comparison with paroxetine in healthy men
2015
Journal of Psychopharmacology
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This was a randomised, doubleblind, four-way crossover, placebo-controlled, multiple-dose study in 24 healthy young men. ...
In the pharmacokinetic/pharmacodynamics analysis significant relationships were found between REM onset latency and time spent in REM sleep and vortioxetine/paroxetine exposure. ...
The relationship, if any, between C av,sleep and the main PSG parameters was investigated by non-linear mixed effect analysis using an E max or a simple linear model. ...
doi:10.1177/0269881115599387
pmid:26253622
pmcid:PMC4579403
fatcat:rn7mkkusqrbibg4aotikzirefu
Pharmacokinetics/Pharmacodynamics Analysis of the Relationship between the in Vivo Micturition Pressure and Receptor Occupancy of (R)-Oxybutynin and Its Metabolite in Rats
2007
Biological and Pharmaceutical Bulletin
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correlations between the receptor occupancies and the PD/safety parameters would be useful to optimize the dose regimen and formulation. 19) In the studies, positron emission tomography (PET) 14, 15) ...
PET studies have an advantage in that they can measure the receptor occupancy directly, however, the synthesis of the positron emission substrate and the system of detection are sometimes impediments to ...
The results of the analysis using the linear inhibitory model, which did not improve the fitting between the effect and the receptor occupancy, compared to the inhibitory effect E max model (data not shown ...
doi:10.1248/bpb.30.955
pmid:17473442
fatcat:ug76vcxga5h4dl7lgckffhow2u
Development of a population pharmacokinetic model to predict brain distribution and dopamine D2 receptor occupancy of raclopride in non-anesthetized rat
2018
European Journal of Pharmaceutical Sciences
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; k on , drug association rate to the receptor; PET, positron emission tomography; PK, pharmacokinetics; RO, receptor occupancy ...
It is one of the most frequently used in vivo D2 tracers (at low doses) for assessing drug-induced receptor occupancy (RO) in animals and humans. ...
We would like to thank Yumi Yamamoto for providing suggestions to the PK model and Dirk-Jan van den Berg for assisting LC − MS analysis of the animal samples. ...
doi:10.1016/j.ejps.2017.10.031
pmid:29106979
fatcat:y5aeinll4ndcfbvxtflzy5egr4
Therapeutic D2/3 receptor occupancies and response with low amisulpride blood concentrations in very late-onset schizophrenia-like psychosis (VLOSLP)
2017
International Journal of Geriatric Psychiatry
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This study aimed to investigate blood drug concentration, D2/3 receptor occupancy, and outcome in VLOSLP during open amisulpride prescribing, and compare this with Alzheimer's disease (AD). ...
imaging was used to estimate D2/3 receptor occupancy. ...
Small sample size meant that it was not possible to fully characterise the non-linear PK-occupancy curve in VLOSLP. ...
doi:10.1002/gps.4758
pmid:28643852
fatcat:eocm6hlpabgxvckydh27spen3y
Determination of receptor occupancy in the presence of mass dose: [11C]GSK189254 PET imaging of histamine H3 receptor occupancy by PF-03654746
2016
Journal of Cerebral Blood Flow and Metabolism
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We developed a method to (1) estimate the in vivo dissociation constant K d of a radioligand from PET studies displaying a non-tracer carryover (NTCO) effect and (2) correct the NTCO bias in occupancy ...
This method was applied in a study of healthy human subjects with the histamine H 3 receptor radioligand [ 11 C]GSK189254 to measure the PK-occupancy relationship of the H 3 antagonist PF-03654746. ...
XL contributed to interpretation of data and statistical analysis. JL contributed to PK analysis and interpretation of data. ...
doi:10.1177/0271678x16650697
pmid:27207170
pmcid:PMC5363483
fatcat:vnuwaf3isre5tnxzl7on4kgat4
Pharmacokinetics and time-course of D2 receptor occupancy induced by atypical antipsychotics in stabilized schizophrenic patients
2008
Journal of Psychopharmacology
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The 123 I-IBZM SPECT measured D 2 receptor occupancy (D 2 RO) in chronically dosed, stabilized schizophrenic patients and its relationship with antipsychotic (AP) pharmacokinetics (PK) over time is still ...
The aims of this study were: 1) To define the relationship between striatal D 2 receptor occupancy (D 2 RO) and plasma concentration (C P ) in stabilized schizophrenic patients on clinically relevant doses ...
Medical Department from GlaxoSmithKline Spain, particularly Juan Lahuerta and Luis Guardiola-Gómez for their support and all the patients who participated in this study. ...
doi:10.1177/0269881107083810
pmid:18308793
fatcat:wtziyas4andtnoqymnat3nn7cm
Padsevonil randomized phase IIa trial in treatment-resistant focal epilepsy – a translational approach
2020
Brain Communications
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Two PET imaging studies were conducted in healthy volunteers to identify optimal padsevonil target occupancy corresponding to levels associated with effective antiseizure activity in rodent models. ...
GABAA receptor occupancy. ...
Acknowledgements The authors express their profound gratitude to the patients who participated in the PoC trial and their families. ...
doi:10.1093/braincomms/fcaa183
pmid:33241213
pmcid:PMC7677606
fatcat:alnxradxezgephs63r5cujvrpy
11C-DPA-713 has much greater specific binding to translocator protein 18 kDa (TSPO) in human brain than 11C-(R)-PK11195
2017
Journal of Cerebral Blood Flow and Metabolism
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Unlike human studies where full receptor blockade is difficult because of possible pharmacological effects, in these monkey studies, we administered the blocking agent to cause full receptor blockade. ...
Receptor occupancy was 31% ± 29% in HABs and 23% ± 18% in MABs. ...
doi:10.1177/0271678x17699223
pmid:28322082
fatcat:dt5aefwsyva73cuxz6amhb6atq
Brain and whole-body imaging in nonhuman primates of [11C]PBR28, a promising PET radioligand for peripheral benzodiazepine receptors
2008
NeuroImage
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The images showed no receptorfree region that could be used for reference tissue analysis. Thus, quantitation of receptor density required measurement of parent radioligand in arterial plasma. ...
The objectives of the current study were to evaluate kinetics of brain uptake, and the influence of the peripheral binding on the arterial input function in rhesus monkey. ...
In vitro receptor screening at all sites other than that labeled with [ 3 H]PK 11195 were performed by the NIMH Psychoactive Drug Screening Program (contract # NO1MH32004). ...
doi:10.1016/j.neuroimage.2007.09.063
pmid:18024084
pmcid:PMC2275117
fatcat:gy4hbqj4yjc7bow4ey3bloemvu
Comparison of D2 dopamine receptor occupancy after oral administration of quetiapine fumarate immediate-release and extended-release formulations in healthy subjects
2011
International Journal of Neuropsychopharmacology
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effect at lower D 2 receptor occupancy than typical antipsychotics. ...
This study investigated if the pharmacokinetic differences translate into different time curves for central D 2 dopamine receptor occupancy. ...
[Clinical trial registration information : Positron emission tomography (PET) study with [ 11 C]raclopride to determine central D 2 dopamine occupancy of SEROQUEL (registration identification no. : NCT00832221 ...
doi:10.1017/s1461145711000514
pmid:21477416
pmcid:PMC3198174
fatcat:zbp5y7sq4fbmnatmc3hk7wfjza
Pharmacology in translation: the preclinical and early clinical profile of the novel α2/3 functionally selective GABAA receptor positive allosteric modulator PF-06372865
2018
British Journal of Pharmacology
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Benzodiazepines, non-selective positive allosteric modulators (PAMs) of GABA A receptors, have significant side effects that limit their clinical utility. ...
PF-06372865 exhibited concentration-dependent occupancy of GABA A receptors in preclinical species. ...
Acknowledgements The authors thank the healthy volunteers who participated in these trials. ...
doi:10.1111/bph.14119
pmid:29214652
fatcat:t52b7hmwwzdu7fqbfpoqz4frci
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