Nathan P.J.,GSK Clinical Unit Cambridge |
Nathan P.J.,University of Cambridge |
Watson J.,Glaxosmithkline |
Lund J.,Glaxosmithkline |
And 15 more authors.
International Journal of Neuropsychopharmacology | Year: 2013
Episodic memory deficits are a core feature of neurodegenerative disorders. Muscarinic M1 receptors play a critical role in modulating learning and memory and are highly expressed in the hippocampus. We examined the effect of GSK1034702, a potent M1 receptor allosteric agonist, on cognitive function, and in particular episodic memory, in healthy smokers using the nicotine abstinence model of cognitive dysfunction. The study utilized a randomized, double-blind, placebo-controlled, cross-over design in which 20 male nicotine abstained smokers were tested following single doses of placebo, 4 and 8 mg GSK1034702. Compared to the baseline (nicotine on-state), nicotine abstinence showed statistical significance in reducing immediate (p=0.019) and delayed (p=0.02) recall. GSK1034702 (8 mg) significantly attenuated (i.e. improved) immediate recall (p=0.014) but not delayed recall. None of the other cognitive domains was modulated by either nicotine abstinence or GSK1034702. These findings suggest that stimulating M1 receptor mediated neurotransmission in humans with GSK1034702 improves memory encoding potentially by modulating hippocampal function. Hence, selective M1 receptor allosteric agonists may have therapeutic benefits in disorders of impaired learning including Alzheimer's disease. © 2012 CINP.
Ziauddeen H.,GSK Clinical Unit Cambridge |
Ziauddeen H.,University of Cambridge |
Ziauddeen H.,Cambridgeshire and Peterborough NHS Foundation Trust CPFT |
Chamberlain S.R.,GSK Clinical Unit Cambridge |
And 25 more authors.
Molecular Psychiatry | Year: 2013
The opioid system is implicated in the hedonic and motivational processing of food, and in binge eating, a behaviour strongly linked to obesity. The aim of this study was to evaluate the effects of 4 weeks of treatment with the mu-opioid receptor antagonist GSK1521498 on eating behaviour in binge-eating obese subjects. Adults with body mass index ≥30 kg m -2 and binge eating scale scores ≥19 received 1-week single-blind placebo run-in, and were then randomized to 28 days with either 2 mg day -1 GSK1521498, 5 mg day -1 GSK1521498 or placebo (N=21 per arm) in a double-blind parallel group design. The outcome measures were body weight, fat mass, hedonic and consummatory eating behaviour during inpatient food challenges, safety and pharmacokinetics. The primary analysis was the comparison of change scores in the higher-dose treatment group versus placebo using analysis of covariance at each relevant time point. GSK1521498 (2 mg and 5 mg) was not different from placebo in its effects on weight, fat mass and binge eating scores. However, compared with placebo, GSK1521498 5 mg day -1 caused a significant reduction in hedonic responses to sweetened dairy products and reduced calorific intake, particularly of high-fat foods during ad libitum buffet meals, with some of these effects correlating with systemic exposure of GSK1521498. There were no significant effects of GSK1521498 2 mg day -1 on eating behaviour, indicating dose dependency of pharmacodynamics. GSK1521498 was generally well tolerated and no previously unidentified safety signals were detected. The potential for these findings to translate into clinically significant effects in the context of binge eating and weight regain prevention requires further investigation. © 2013 Macmillan Publishers Limited.
The safety, tolerability, pharmacokinetics and cognitive effects of GSK239512, a selective histamine H₃ receptor antagonist in patients with mild to moderate Alzheimers disease: a preliminary investigation
PubMed | GSK Clinical Unit Cambridge
Type: Journal Article | Journal: Current Alzheimer research | Year: 2013
The histamine H3 receptor plays a critical role in the negative neuromodulation of neurotransmitters involved in cognitive function. H3 receptor antagonists/inverse agonists have been shown to exert pro-cognitive effects in pre-clinical models. GSK239512 is a potent and selective H receptor antagonist developed for the treatment of cognitive dysfunction in neurodegenerative disorders. In this study we examined the safety, tolerability, pharmacokinetics and pro-cognitive effects of GSK239512 (oral) in patients with mild to moderate Alzheimers disease using ascending dose titration regimens.The study was conducted in two parts. Part A was a single-blind, placebo run-in, flexible dose titration over 9 days in two cohorts, each consisting of two patients. Part B was a double-blind, randomised, placebo controlled, parallel group, which investigated 3 flexible dose titration regimens over 4 weeks in 3 cohorts, each consisting of eight patients.Overall, the 5/10/20/40 g and 10/20/40/80 g regimens were well-tolerated. The regimen of 20/40/80/150 g showed the poorest tolerability likely due to the higher starting dose. There were no clinically significant abnormalities in haematology, clinical chemistry, urinalysis parameters and cardiovascular parameters. GSK239512 had positive effects on tasks of attention and memory with effect sizes between 0.56 and 1.37.GSK239512 displayed asatisfactory level of tolerability in patients with Alzheimers disease with evidence for positive effects on attention and memory. The findings suggest that a titration regimen with a starting dose of 5-10 g and a maximum dose of 80 g is likely to be a well-tolerated and potentially efficacious regimen for future clinical trials in patients with Alzheimers disease. These findings await replication in a larger study.