‘Improving health and wellbeing through Research’ Preston Football Club 17 th October 2014
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Transcript of ‘Improving health and wellbeing through Research’ Preston Football Club 17 th October 2014
‘Improving health and wellbeing
through Research’
Preston Football Club17th October 2014
Improving health and wellbeing through research – October 2014
Dr Salman KarimConsultant Psychiatrist
“Dementia Clinical Trials”
Theme:Developing
Clinical Research
Improving health and wellbeing through research – October 2014
Clinical Trials in Alzheimer's Disease
Dr Salman KarimConsultant Psychiatrist/Honorary Senior
Lecturer
Lancashire Care NHS Foundation Trust
University of Manchester
EPIDEMIOLOGY
• 700,000 people in UK• 17-25 million people worldwide• Expected to rise to 30-40 million• Incidence reported higher in the west (2%)• Prevalence doubles every 5 years
below 5% in 30-65 years
above 10% in over 80 years
EPIDEMIOLOGY
• Cost of care in UK is 4 billion per year• In North America its 100 billion dollars• 25% hospital cost• 75% residential care cost• Does not include carers burden• Phenomenal rise expected in future
RISK FACTORS
• Age
Risk doubles every 5 years after 60• Genetic predisposition (ApoE E4)
Inability to remove amyloid plaque
Tau accumulation
Loss of neurons • Vascular risk factors• Head trauma
NEUROPATHOLOGY
• Senile Plaques :
Extra-cellular amyloid beta-peptide
• Neurofibrillary Tangles :
Intra-cellular fibrillary proteins• Reduction of neurons and synapses• Reduction in cellular energy metabolism• Neuronal dysfunction/ death
Neurotoxic action of Beta amyloid
• Oxidative stress• Impaired cellular metabolism• Mitrochondial dysfunction• Impaired calcium metabolism• Impairment of long term potentiation• Increased neuro-fibrillary tangle formation
Neurochemistry of Alzheimer’s disease
Acetylcholine:• Perception, Attention, Learning, attention,
Cognition and judgement
Noradrenaline:• Alertness, Memory and Attention
Serotonin:• Regulation of appetite and emotions
Glutamate (excitatory neurotransmitter ):• Neuronal cell death in many conditions is mediated
by the effects of glutamate
MANAGEMENT
• Medications
Cholinesterase inhibitors (Donepezil, Rivastigmine, Galantamine)
Memantine
• Non pharmacological interventions
Developing New Drugs for Alzheimer's Disease
Identifying target areas:• Beta amyloid clearance• Tau protein clearance• Enhancing neurotransmission
Developing biological makers of AD:• Blood markers• CSF markers• Imaging
Challenges
Cost of developing new drugs• Average cost 1.2 billion including failures• 101 clinical trials on AD since 1998• 3 drugs licenced
Time scale• Drug discovery/preclinical: 3-6 years• Clinical trials (phase I, II and III): 6-7 years• Licensing: 0.5-2 years
Local Challenges
Increasing complexity of protocols• Physical investigations (bloods, ECG,
Imaging, CSF)• Pharmacy • Facilities
Developing the team with skill mix• Medical staff• Nursing staff• Skilled raters
Local Challenges
• Staff Training• Bureaucracy• Developing partnerships• Risks/benefits
Clinical Trials in LCFT
Nicotinic receptor targeted trials:• RCT to evaluate the efficacy and safety of
ABT-126 in mild to moderate AD.• Long-term safety and tolerability of ABT-
126 in mild-to-moderate AD.• RCT to evaluate safety and sfficacy of
ABT-126 in Cognitive Deficits in Schizophrenia.
Neuronal Nicotinic Receptors
α7 Receptors: Pre- and Postsynaptic Mechanisms
ChAT
NT
NT
Cholinergic Neuron
Target Neuron
Effector Neuron
NT
Choline +
Acetyl-CoA
ACh
AChACh
AC
h
α7
NT
Na+ NT
NT
NT
ChATCholine + Acetyl-CoA
ACh
NT
NT
α7 activation ↑ neurotransmitter release e.g. ACh, glutamate, GABA, serotonin, and dopamine
α7 activation ↑ neurotransmitter release e.g. ACh, glutamate, GABA, serotonin, and dopamine
α7
α7
Na+
Ca++
Ca++
ERK CREB
ACh
Activation of
presynaptic a7 nicotinic receptors potentiates synaptic transmission
Activation of
presynaptic a7 nicotinic receptors potentiates synaptic transmission
Ca++
Cholinergic Neuron
ACh
Reviewed in: Stahl SM. J Clin Psychiatry. 2000;61(9):628-9. Bitner RS, Nikkel AL, et al., Brain Research. 2009;1265:65-74.
Postsynaptic α7 Receptors
Presynaptic α7 Receptors
↑ intracellular Ca++ activates pro-cognitive signal transduction pathways
Na+
ACh
ACh
ACh
ACh
ACh
ACh
ACh
α7ERK CREB
Ca++
= ACh, Glu, GABA, 5-HT, DA
NT
Clinical Trials in LCFT
• Increased cortisol in AD• ABT-384 is a selective 11-β-
hydroxysteroid dehydrogenase type 1 (HSD-1) inhibitor
• RCT to evaluate the efficacy and safety of ABT-384 in subjects with Mild-to Moderate Alzheimer’s Disease
Clinical Trials in LCFT
• Novel Histamine H3 receptor antagonist S38093
• Efficacy and safety of S38093 Vs placebo in co-administration with donepezil in patients with moderate AD. A 24 week international, multi-centre, randomised, double-blind, placebo-controlled phase IIb study
S38093
Clinical Trials in LCFT
5HT6 receptor antagonist (Lu AE58054) blocking GABA-ergic excitation• RCT of Lu AE58054 in patients with mild-
moderate Alzheimer’s disease treated with an acety-cholinesterase inhibitor.
Clinical Trials in LCFT
• Mono-clonal antibodies (beta amyloid removal)
• RCT of efficiency and safety of Gantenerumab in subjects with mild AD.
• RCT of efficiency and safety of Gantenerumab in subjects with mild AD: PET scan sub study.
Vision for Future
• To develop a clinical research facility• To expand clinical trials portfolio• To build a team of researchers
Thank you!
Karen PalmerClinical Research Nurse Manager
“What our nurses can offer you”
Theme:Developing
Clinical Research
Improving health and wellbeing through research – October 2014
Karen Palmer – Clinical Research Nurse Manager
Kelly Wigglesworth – Research Nurse Daniel Pulford – Clinical Studies Officer Andrea Houlding – Research Secretary
Sit within the Corporate Network under the Research department and are a generic trust research resource.
The Team
We provide support to clinical services who are approved to conduct a NIHR portfolio adopted research study.
Support is tailor made to researchers needs.
Including educational support for researchers and clinical staff. Along with the conduct of all clinical and administrative aspects of the research process.
The Service
The NIHR (National Institute for Health Research) requires Trusts to conduct high
quality research.
This is research which is grant funded through competitive means and has been adopted onto
a portfolio of registered national projects.
These projects are monitored against their achievement of the recruitment target and the
delivery of the research findings
What is the NIHR Portfolio?
All NIHR Portfolio adopted studies can be found on the UK Clinical Research Network (UKCRN) Portfolio website:
http://public.ukcrn.org.uk/search/
Where to find portfolio studies
Contact the Research department at [email protected] and quote the following information: Project reference number (as shown on
the website) Project title The team will then make contact with the
researcher on your behalf and request further information. This information can be assessed jointly and a decision can be made on the services ability to support the study and staff capacity
What to do if you want to know more about a study
Views of a participant and Carer
Please click:‘A participants experience of Dementia Research’
A portfolio research study is identified to sit within you clinical team
A review of resources will
take place between you
and the research dept to facilitate
the research
If a need is identified the research dept
will refer you to the research
nurses
How to register an interest for assistance
Any questions?