Alzheimers Disease Therapeutics Approaches - PowerPoint PPT Presentation

Loading...

PPT – Alzheimers Disease Therapeutics Approaches PowerPoint presentation | free to view - id: 1c3990-ZDc1Z



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

Alzheimers Disease Therapeutics Approaches

Description:

Alzheimer 's Disease Research Center, France. MEDICAL TREATMENT ... delusion placebo (p = 0,048) Cas observ s LOCF 6 mois. Galantamine placebo. placebo galantamine ... – PowerPoint PPT presentation

Number of Views:95
Avg rating:3.0/5.0
Slides: 28
Provided by: Chu159
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: Alzheimers Disease Therapeutics Approaches


1
Alzheimer s Disease Therapeutics Approaches
  • B.Vellas M.D, Ph.D
  • Alzheimer s Disease Research Center, France

2
MEDICAL TREATMENT
  • Acethyl-cholinesterase Inhibitors
  • Memantine.

3
Cholinergic Pathways Implicated in Alzheimers
Disease
Medial Septum and Diagonal Band of Broca
Nucleus Basalis of Meynert
4
Approved Cholinesterase Inhibitors
5
Cholinergic Treatment of Alzheimers Disease
  • Produces measurable improvement in cognition and
    caregivers and physicians impression
  • Effect is modest equivalent to a 6-12 month
    delay
  • Behavioral and functional effects
  • Unclear if it alters the progression of
    neurodegeneration
  • Long-term effects need to be clarified
  • Effects also in severe dementia
  • Switch Studies

6
Mechanism of Actions
7
I AchE
8
Donepezyl
Inhibition maximale de lAChE à 10 mg / jour
5 mg/j 63,6 10 mg/j 77,3 (1)
Rogers SL et al. A 24-
9
Donepezyl
  • Efficacy on
  • Cognitive functions
  • global functioning
  • Activities Daily Living
  • For the patient
  • Autonomy
  • Quality of life
  • delay to Institutionnalisation

10
Cognitive Functions

Rogers S.L. et al.
11
Functional Status
Un gain de 5 mois en moyenne sur 1 an
12
Long-term effect
Rogers SL et al.. Long-term efficacy and safety
of donepezil in the treatment of Alzheimers
disease final analysis of a US multicentre
open-label
13
If the treatment is stopped at 6 Months
14
Neuro Psychiatry Inventory (NPI)
  • 6 Months )
  • Apaty and anxiety galantamine (p lt 0,0001)
  • delusion placebo (p 0,048)

Cas observés LOCF à 6 mois Galantamine
placebo placebo galantamine
15
Results at 3 years
16
(No Transcript)
17
Résultats
  • Survie
  • Temps médian 77 mois tous patients confondus
  • Temps médian 83 mois pour patients AD
  • Temps médian 84 mois ayant reçu la Galantamine
    pendant au moins 1 ans (quelque soit la durée du
    traitement)
  • Faiblesses
  • Étude rétrospective, non contrôlée ? biais de
    sélection
  • MAIS, analyse multivariée pour rendre résultats
    valides

18
(No Transcript)
19
Schwalen, results at 48 months
  • Results
  • After 36 months
  • After 48 months

20
Glutamate and Alzheimer
hyperstimulation of NMDA receptors by the
glutamate
glutamate neurotoxic
Danysz W et al. Neuroprotective and
symptomatological action of memantine relevant
for Alzheimer s disease - A unified
glutamatergic hypothesis on the mechanismof
action. Neurotoxicity Research 2000 2
85-97. Cacabelos R. The glutamatergic system and
neurodegeneration in dementia preventive
strategies in Alzheimers disease.Int J Geriat
Psychiatry 1999 14 3-47.
21
Mémantine First non competitive antagonist OF
NMDA receptors in Alzheimer

Mémantine un nouveau mode daction
Mémantine la restauration de la transmission
neuronale
Danysz W et al. Neuroprotective and
symptomatological action of memantine relevant
for Alzheimer s disease - A unified
glutamatergichypothesis on the mechanism of
action. Neurotoxicity Research 2000 2 85-97.
22
Schéma de létude
Etude MRZ-9605 USA Ambulatoire.
Etude Reisberg
  • Etude
  • Nombre de patients(en intention de traiter)
  • Diagnostic
  • Age (moyenne)
  • Severity
  • Dose journalière
  • Durée
  • Critères primaires defficacité
  • Critères secondaires defficacité
  • Randomisée, multicentrique, double insu versus
    placebo
  • n 252 patients à domicile
  • Démence Alzheimer (DSM IV)
  • ? 50 ans (76)
  • MMSE 314 GDS 5-6
  • 20 mg / jour
  • 28 semaines
  • CIBIC-plusADCS ADLsev
  • SIB, RUD, FAST, MMSE, GDS et NPI

Reisberg et al, Memantine in moderate to severe
Alzheimers disease, NEJM, 2003, 34814
23
CIBIC-PLUS
4,0
Mémantine
4,2
4,4
Aggravation
Score global CIBIC-plus
Placebo
4,6
4,8
5,0
0
12
Fin d'étude LOCF
28 OC
Semaine
Mémantine
n 126
107
97
118
Placebo
n 126
105
84
118
p 0,03
p 0,06 (ns)
OC Observed cases LOCF Last Observation
Carried Forward
Reisberg et al, Memantine in moderate to severe
Alzheimers disease, NEJM, 2003, 34814
24
ADCS-ADLsev
1
Amélioration
Mémantine
Aggravation
Différence de score ADCS-ADLsev
Placebo
- 4
- 5
- 6
- 7
4
0
12
Fin d'étude LOCF
28 OC
Semaine
Mémantine
n 126
107
97
124
119
Placebo
n 126
106
84
123
117
p 0,003
p 0,02
OC Observed cases LOCF Last Observation
Carried Forward
Reisberg et al, Memantine in moderate to severe
Alzheimers disease, NEJM, 2003, 34814
25
SIB
2
Amélioration
Mémantine
Aggravation
Différence de score SIB
Placebo
- 12
0
12
Fin d'étude LOCF
28 OC
4
Semaine
Mémantine
n 126
107
96
124
119
Placebo
n 126
106
83
123
117
p 0,002
p lt 0,001
OC Observed cases LOCF Last Observation
Carried Forward
Reisberg et al, Memantine in moderate to severe
Alzheimers disease, NEJM, 2003, 34814
26
Combination therapy
  • Some improvment in patients with both AcheI and
    Memantine (JAMA 2004)
  • Cost ?
  • When to start ? When to stop ?

27
Docosahexaenoic Acid (DHA) Epidemiological Studies
  • Autopsy study - PUFA content, including DHA, was
    decreased in the hippocampus and frontal gray
    matter of AD brains (Söderberg et al. 1991)
  • Framingham cohort - low DHA was a predictor of AD
  • (Kyle et al. 1999)
  • Rotterdam study - fish consumption, a marker of
    n-3 PUFAs including DHA, was associated with a
    lower risk of developing AD
  • (Kalmijn et al. 1997)
About PowerShow.com