Abstract
Background: 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 H3 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 Alzheimer’s disease using ascending dose titration regimens.
Methods: 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.
Results: Overall, the 5/10/20/40μg and 10/20/40/80μg regimens were well-tolerated. The regimen of 20/40/80/150μg 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.
Conclusions: GSK239512 displayed asatisfactory level of tolerability in patients with Alzheimer’s disease with evidence for positive effects on attention and memory. The findings suggest that a titration regimen with a starting dose of 5-10μg and a maximum dose of 80μg is likely to be a well-tolerated and potentially efficacious regimen for future clinical trials in patients with Alzheimer’s disease. These findings await replication in a larger study.
Keywords: Alzheimer’s disease, attention, cognition, H3 receptor, histamine, antagonist, memory, safety, tolerability
Current Alzheimer Research
Title:The Safety, Tolerability, Pharmacokinetics and Cognitive Effects of GSK239512, a Selective Histamine H3 Receptor Antagonist in Patients with Mild to Moderate Alzheimer’s Disease: A Preliminary Investigation
Volume: 10 Issue: 3
Author(s): Pradeep J. Nathan, Rebecca Boardley, Nicola Scott, Alienor Berges, Paul Maruff, Tharani Sivananthan, Neil Upton, Martin T. Lowy, Peter J. Nestor and Robert Lai
Affiliation:
Keywords: Alzheimer’s disease, attention, cognition, H3 receptor, histamine, antagonist, memory, safety, tolerability
Abstract: Background: 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 H3 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 Alzheimer’s disease using ascending dose titration regimens.
Methods: 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.
Results: Overall, the 5/10/20/40μg and 10/20/40/80μg regimens were well-tolerated. The regimen of 20/40/80/150μg 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.
Conclusions: GSK239512 displayed asatisfactory level of tolerability in patients with Alzheimer’s disease with evidence for positive effects on attention and memory. The findings suggest that a titration regimen with a starting dose of 5-10μg and a maximum dose of 80μg is likely to be a well-tolerated and potentially efficacious regimen for future clinical trials in patients with Alzheimer’s disease. These findings await replication in a larger study.
Export Options
About this article
Cite this article as:
J. Nathan Pradeep, Boardley Rebecca, Scott Nicola, Berges Alienor, Maruff Paul, Sivananthan Tharani, Upton Neil, T. Lowy Martin, J. Nestor Peter and Lai Robert, The Safety, Tolerability, Pharmacokinetics and Cognitive Effects of GSK239512, a Selective Histamine H3 Receptor Antagonist in Patients with Mild to Moderate Alzheimer’s Disease: A Preliminary Investigation, Current Alzheimer Research 2013; 10 (3) . https://dx.doi.org/10.2174/1567205011310030003
DOI https://dx.doi.org/10.2174/1567205011310030003 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
Call for Papers in Thematic Issues
New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease
Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address ...read more
Current updates on the Role of Neuroinflammation in Neurodegenerative Disorders
Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
Deep Learning for Advancing Alzheimer's Disease Research
Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our ...read more
Diagnostic and therapeutic biomarkers of dementia
Dementia affects 18 million people worldwide. Dementia is a syndrome of symptoms caused by brain disease, usually chronic or progressive, clinically characterized by multiple impairments of higher cortical functions such as memory, thinking, orientation, and learning. In addition, in the course of dementia, cognitive deficits are observed, which often hinder ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Vitamin D and Metabolic Syndrome: Is There a Link?
Current Pharmaceutical Design Meningococcal Disease and Future Drug Targets
CNS & Neurological Disorders - Drug Targets Diabetes and Parkinson’s Disease: Debating the Link Through Ca2+/cAMP Signalling
Current Diabetes Reviews Modulation of GABAA Receptors by Natural Products and the Development of Novel Synthetic Ligands for the Benzodiazepine Binding Site
Current Drug Targets Phenolic Acids Exert Anticholinesterase and Cognition-Improving Effects
Current Alzheimer Research Could Better Phenotyping Small Vessel Disease Provide New Insights into Alzheimer Disease and Improve Clinical Trial Outcomes?
Current Alzheimer Research Therapeutic Angiogenesis using Hepatocyte Growth Factor (HGF)
Current Gene Therapy Reduction in Vascular Endothelial Growth Factor Expression in the Superior Temporal, Hippocampal, and Brainstem Regions in Alzheimer`s Disease
Current Neurovascular Research Neuroinflammation: A Therapeutic Target of Cotinine for the Treatment of Psychiatric Disorders?
Current Pharmaceutical Design L-Carnitine - Metabolic Functions and Meaning in Humans Life
Current Drug Metabolism Editorial (Hot Topic : Computational Prediction of Drug-Target Interactions in Medicinal Chemistry)
Current Topics in Medicinal Chemistry subject Index To Volume 1
Current Drug Targets - Inflammation & Allergy Microdose Lithium Treatment Stabilized Cognitive Impairment in Patients with Alzheimer’s Disease
Current Alzheimer Research Exploring the Role of Gene Therapy for Neurological Disorders
Current Gene Therapy Smoking and Hypertension: Independent or Additive Effects to Determining Vascular Damage?
Current Vascular Pharmacology Enteric Ecosystem Disruption in Autism Spectrum Disorder: Can the Microbiota and Macrobiota be Restored?
Current Pharmaceutical Design Modelling Decline in Cognition to Decline in Function in Alzheimer’s Disease
Current Alzheimer Research Semantic Memory Disorders in Alzheimers Disease: Clues from Semantic Priming Effects
Current Alzheimer Research Biomarkers of Cell Damage Induced by Oxidative Stress in Parkinsons Disease and Related Models
Central Nervous System Agents in Medicinal Chemistry Cystathionine Beta Synthase as a Risk Factor for Alzheimer Disease
Current Alzheimer Research