A Randomized, Double-blind, Placebo-controlled, Crossover Study to Evaluate the Influence of the A118G Polymorphism in the mu Opioid Receptor Gene (OPRM1) on Effects of GSK1521498 and Naltrexone on Physiological and Behavioural Markers of Brain Function in Healthy Social Drinkers

A total of at least 48 healthy subjects with a history of social drinking will be recruited into this single-centre, randomized, double-blind, cross-over study. Subjects will be genetically stratified to result in equal numbers of A118G 'AA' homozygotes (n=24) and A118G 'G' carriers (n=24).
Subjects will participate in all three treatment periods and will be randomized to receive each of the following for 5 days: Treatment A: Placebo, Treatment B: Naltrexone (NTX) 50 mg once daily (25 mg once daily for the first two days) and Treatment C: GSK1521498 10 mg once daily. A washout period will be of at least 14 days between treatments. Subjects will return for a follow-up visit 7-10 days after the final treatment session washout period has been completed.
Subjects will attend the clinical research unit on days 1, 2, 3, 4 and 5 to monitor safety and tolerability for both drugs. Subjects will attend the clinical unit on days 4 and 5 for a two day assessment, using a series of pharmacodynamic measurements known to be sensitive to the effects of GSK1521498 and/or NTX: Functional brain response to alcohol and food cues; plasma cortisol; hedonic and consummatory eating behaviors; subjective response to an ethanol challenge; experimental pain threshold; and cognitive tests of attention bias towards alcohol and food cues.

开始日期2012-12-12

申办/合作机构

GSK Plc

NCT01366573 / Completed临床1期

A Randomised, Double-Blind, Single-Dose, Four-Period Cross-Over Study to Determine the Effects of Alcohol on the Pharmacokinetics and Pharmacodynamics of GSK1521498 in Healthy Subjects

The aim of the study is to assess the safety and tolerability of GSK1521498 in combination with alcohol and to determine the amount of GSK1521498 and alcohol in your blood after you have been given these together. The study will also determine whether GSK1521498 will have an effect on alcohol liking and consumption.

开始日期2011-05-13

申办/合作机构

GSK Plc

[+1]

NCT01195792 / Completed临床2期

A 35-Day, Multi-Centre, Randomised, Parallel-Group, Double-Blind, Placebo-Controlled Proof of Concept Study to Investigate the Effects of GSK1521498 on Body Weight and Composition, Eating Behaviour and Related Brain Function, in Obese Subjects With Over-Eating Behaviours.

The purpose of this study is to determine whether GSK1521498 will cause weight loss in obese but otherwise healthy subjects with over-eating behaviours.

开始日期2010-09-01

申办/合作机构

GSK Plc

100 项与 GSK-1521498 相关的临床结果

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100 项与 GSK-1521498 相关的转化医学

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100 项与 GSK-1521498 相关的专利（医药）

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项与 GSK-1521498 相关的文献（医药）

2024-09-01·European Journal of Nuclear Medicine and Molecular Imaging

Total-body imaging of mu-opioid receptors with [11C]carfentanil in non-human primates

Article

作者: Dubroff, Jacob G ; Hou, Catherine ; Lee, Hsiaoju ; Tomita, Cosette ; Hsieh, Chia-Ju ; Mach, Robert H ; Schmitz, Alexander ; Plakas, Konstantinos

AbstractPurposeMu-opioid receptors (MORs) are widely expressed in the central nervous system (CNS), peripheral organs, and immune system. This study measured the whole body distribution of MORs in rhesus macaques using the MOR selective radioligand [11C]carfentanil ([11C]CFN) on the PennPET Explorer. Both baseline and blocking studies were conducted using either naloxone or GSK1521498 to measure the effect of the antagonists on MOR binding in both CNS and peripheral organs.MethodsThe PennPET Explorer was used for MOR total-body PET imaging in four rhesus macaques using [11C]CFN under baseline, naloxone pretreatment, and naloxone or GSK1521498 displacement conditions. Logan distribution volume ratio (DVR) was calculated by using a reference model to quantitate brain regions, and the standard uptake value ratios (SUVRs) were calculated for peripheral organs. The percent receptor occupancy (%RO) was calculated to establish the blocking effect of 0.14 mg/kg naloxone or GSK1521498.ResultsThe %RO in MOR-abundant brain regions was 75–90% for naloxone and 72–84% for GSK1521498 in blocking studies. A higher than 90% of %RO were observed in cervical spinal cord for both naloxone and GSK1521498. It took approximately 4–6 min for naloxone or GSK1521498 to distribute to CNS and displace [11C]CFN from the MOR. A smaller effect was observed in heart wall in the naloxone and GSK1521498 blocking studies.Conclusion[11C]CFN total-body PET scans could be a useful approach for studying mechanism of action of MOR drugs used in the treatment of acute and chronic opioid use disorder and their effect on the biodistribution of synthetic opioids such as CFN. GSK1521498 could be a potential naloxone alternative to reverse opioid overdose.

2021-05-01·Psychopharmacology3区 · 医学

Lessons learned from using fMRI in the early clinical development of a mu-opioid receptor antagonist for disorders of compulsive consumption

3区 · 医学

Review

作者: Bakker, Geor ; Nathan, Pradeep J

Functional magnetic resonance imaging (fMRI) has been widely used to gain a greater understanding of brain circuitry abnormalities in CNS disorders. fMRI has also been used to examine pharmacological modulation of brain circuity and is increasingly being used in early clinical drug development as functional pharmacodynamic index of target engagement, and to provide early indication of clinical efficacy. In this short review, we summarize data from experimental medicine and early clinical development studies of a mu-opioid receptor antagonist, GSK1521498 developed for disorders of compulsive consumption including binge eating in obesity. We demonstrate how fMRI can be used to answer important questions of early clinical drug development relating to; (1) target engagement, (2) dose response relationships, (3) differential efficacy and (4) prediction of behavioural and clinically relevant outcomes. We also highlight important methodological factors that need to be considered when conducting fMRI studies in drug development given the challenges faced with small sample sizes in Phase 1 and early proof of mechanism studies. While these data highlight the value of fMRI as a biomarker in drug development, its use for making Go/No-go decisions is still faced with challenges given the variability of responses, interpretation of brain activation changes and the limited data linking drug induced changes in brain activity to clinical or behavioural outcome. These challenges need to be addressed to fulfil the promise of fMRI as a tool in clinical drug development.

2018-03-01·Neuropsychopharmacology1区 · 医学

Compulsive Seekers: Our take. Two Clinicians’ Perspective on a New Animal Model of Addiction

1区 · 医学

Article

作者: Epstein, David H ; Kowalczyk, William J

The rat model of alc. seeking described by Giuliano and colleagues (this issue)-we will refer to it as the Giuliano model-is part of a welcome trend toward animal models that incorporate two cardinal features of human addiction, which are as follows: (a) the use of drugs despite an unfavorable ratio of benefits to harms and (b) the fact that only a minority of drug users become addicted.Rats in the Giuliano model were trained on a chained schedule of reinforcement, so their seeking of alc. (via a lever that made a second lever accessible) could be tested and manipulated sep. from their taking of alc. (via the second lever, which brought the opportunity to drink).The model was intended to provide a platform whereby interventions could break the seeking/taking chain at the earliest possible point.Giuliano and colleagues used an alc.-preferring strain of rats, all of which were initially given a two-bottle (alc./water) choice task to confirm and quantify their bibulosity.All were then trained to acquire the seeking/taking response chain, using a random-interval 60-s schedule for seeking-lever reinforcement and an FR1 schedule for taking-lever reinforcement.With seeking/taking established, one group of rats was assigned to an 'instrumental exposure' condition (eight 2-h sessions, in which the taking lever was presented alone, with the FR1 schedule still in effect), and a smaller group was assigned to a 'one-bottle exposure' condition (eight 4-h sessions in which the alc. solution was simply available for drinking in the home cage-which presumably resulted in greater lifetime exposure, though the difference is not reported).Both groups then underwent a 'seeking-taking punishment phase,' in which the initial training conditions were modified so that 30% of responses on the seeking lever resulted in footshock instead of access to the taking lever.Rats were heterogeneous in their responses to this intermittent punishment.Using cluster anal., Giuliano and colleagues sorted the rats into those that persisted on the seeking lever ('compulsive' rats, 34%), those that greatly reduced their seeking ('non-compulsive' rats, 30%), and those that were 'intermediate' (the other 36%).These phenotypes remained largely stable for 10 mo of testing.They were not accounted for by baseline differences on the two-bottle alc./water choice, nor by history of alc. exposure (ie, home-cage access vs only instrumental access).For 10 mo after the punishment phase, the rats underwent an array of tests.In a progressive-ratio task using the taking lever only, the 'compulsive' rats had a higher breakpoint than the 'intermediate' and 'non-compulsive' rats.In a test of reinstatement after extinction, alc.-related cues reinstated responding on the seeking lever, especially for the 'intermediate' rats.Reinstated responding on the taking lever (presented after a seeking-lever response) did not clearly differ by compulsiveness phenotype, suggesting that the differential susceptibility to reinstatement was specific to seeking.In sep. tests, seeking-lever presses were reduced by systemic administration of the mu-opioid antagonist GSK1521498.The extent of the reduction seemed to vary complexly across 'compulsive,' 'intermediate' and 'non-compulsive' rats, and as a function of their behavioral history.Giuliano and colleagues emphasize that the reduction looked especially prominent in the 'compulsive' rats.

100 项与 GSK-1521498 相关的药物交易

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