TREATMENT OF ALZHEIMER’S DISEASETransdermal treatment – The rivastigmine patch (Exelon®) is the first transdermal treatment for Alzheimer’s disease – The therapeutic dosage

TREATMENT OF ALZHEIMER’S DISEASE

Post synaptic

Acetyl CoA+

Choline

Choline+

AcetateAChE

ACh

ACh

ChAT

Central Cholinergic Synapse

X

Cholinesterase Inhibitors

(-)

M2

Muscarinic 1receptor

(+)

ALZHEIMER DISEASE: ALZHEIMER DISEASE: PHARMACOLOGICAL APPROACHESPHARMACOLOGICAL APPROACHES

AcetylcholineAcetylcholine

ChE inhibitorsChE inhibitorsMuscarinic or nicotinic Muscarinic or nicotinic agonistsagonists

ββ-amyloid-amyloid

Alter APP formationAlter APP formationBlock b-amyloid formationBlock b-amyloid formationInhibit b-amyloid aggregationInhibit b-amyloid aggregationImmunizationImmunization

EstrogenEstrogenAntioxidantsAntioxidantsNSAIDsNSAIDsCell cycle inhibitorsCell cycle inhibitors

GlutamateGlutamate

MemantineMemantine

AchE inhibitors in mild to moderate Alzheimer’s disease

Cholinesterase inhibitors: Cholinesterase inhibitors: a rational therapeutic approach in ADa rational therapeutic approach in AD

NH2

N

Mechanism: AChE/BuChE-IInhibition: reversible

Tacrine

O

OON

Mechanism: AChE-IInhibition: reversible

Donepezil

N

O

O

NN

H

Mechanism: AChE/BuChE-IInhibition: pseudo-irreversible

Physostigmine

OO

O

OHP

ClCl Cl

O

OO

O

PCl

Cl

Mechanism: AChE/BuChE-IInhibition: irreversible

Metrifonate

OO

HH

N

OH

Mechanism: AChE-IInhibition: reversible

Galantamine

O

O N

N

Mechanism: AChE/BuChE-IInhibition: pseudo-irreversible

Rivastigmine

Weinstock, 1999

Both AChE and BuChE break down Both AChE and BuChE break down ACh in the brainACh in the brain

3. AChE + BuChEhydrolyse ACh

1. Electrical impulse triggers ACh release

2. ACh diffuses towards ACh receptors on the post-synaptic neuron

ACh

4. ACh acetic acid + choline

5. Return to the pre-synaptic neuron, regenerating ACh

Presynapticneuron

Postsynapticneuron

AChE=acetylcholinesteraseBuChE=butyrylcholinesterase

Butyrylcholinesterase Butyrylcholinesterase (BuChE)(BuChE) BuChE BuChE and and acetylcholinesterase (AChEacetylcholinesterase (AChE) are ) are

members of the same family of enzymesmembers of the same family of enzymes

Both AChE and BuChE regulate the Both AChE and BuChE regulate the neurotransmitter acetylcholine (ACh) in the neurotransmitter acetylcholine (ACh) in the brainbrain

Likely to play a key role (rather than just a Likely to play a key role (rather than just a back-up role) in improving cholinergic back-up role) in improving cholinergic neurotransmissionneurotransmission

Mesulam et al. 2002; Darvesh et al. 2003

Distribution of cholinesterases Distribution of cholinesterases in the healthy human brainin the healthy human brain

Mesulam, 2000Darvesh et al. 1998

AChE neurons are abundant in the brain BuChE is rich in limbic areas (amygdala, hippocampus and thalamus)

Amygdala

Hippocampus

Plate 1 Plate 2

AChEBuChE

Distribution of cholinesterases in Distribution of cholinesterases in the healthy human brainthe healthy human brain

BuChE activity increases in the AD brain

AChE activity decreases and relative BuChE activity increases in the AD brain

P

AChE activity decreases and BuChE activity AChE activity decreases and BuChE activity increases with disease progressionincreases with disease progression

BuChE activity increases by 40–90% as the disease BuChE activity increases by 40–90% as the disease progresses, while AChE activity decreases by 45%progresses, while AChE activity decreases by 45%11

AChE BuChE

Time (progression of disease)

Enzy

me

activity

Perry et al. 1978

BuChE activity increases in the AD brain, compared with healthy controls

BuChE staining in the temporal cortex of a 71 year-old patient with AD. BuChE is found in plaques (), tangles ( ), dystrophic neurites ( ), and glia ()

BuChE staining in an 89 year-old non-demented individual. BuChE staining is limited to the glia ()

Guillozet et al. 1997

Relation between ChE activity and Relation between ChE activity and numbers of senile plaques in the cerebral numbers of senile plaques in the cerebral cortexcortex

0

20

40

60

80

100

120

140

160

180

200

0 1–5 6–10 11–20 21–30 31–42

Mean plaque count

Act

ivity

rela

tive

to gro

up w

ith

no p

laqu

es (%

)

BuChE

AChE

ChAT

Perry et al. 1978bChE=cholinesterase

DementiaDementia** patients with ‘less active’ BuChE patients with ‘less active’ BuChE (e.g. k-variant) have slower disease progression(e.g. k-variant) have slower disease progression

CAMCOG=Cambridge Cognitive Examination*Moderate to severe patients diagnosed with DLB or AD

p=0.04

O’Brien et al. 2003

18

16

14

12

10

8

6

4

2

0

Wild-type BuChE (n=19)

K-variant BuChE (n=6)

Ann

ual c

hang

e in

CA

MC

OG

sco

re

Decline

Activity of BuChE and AActivity of BuChE and Aββ deposition in AD cortexdeposition in AD cortex

Cer

ebra

l BuC

hE a

ctiv

ity

(nm

ol x

min

–1 x

mg–

1 pro

tein

)

0 50 100 150 200

1.50

1.25

1.00

0.75

0.50

Density of Ab deposition in neocortical area 8 (mm–3)

r=0.86

Arendt et al. 1992

Inhibition of either AChE or BuChE in the brain Inhibition of either AChE or BuChE in the brain increases ACh concentrationincreases ACh concentration

BuChEinhibition*

0

20

40

60

80

100

0(control)

50 µM 170 µM

Specific BuChE inhibitor (MF-8622)

Extr

acel

lula

r AC

hco

ncen

trat

ion

(nM

)

AChEinhibition*

0

20

40

60

80

100

0(control)

1.3 µM 5.3 µM

Specific AChE inhibitor (Donepezil)

Extr

acel

lula

r AC

h co

ncen

trat

ion

(nM

)

*Preclinical studies Giacobini et al. 1996

AChE AChE oror BuChE specific inhibitors BuChE specific inhibitors improve cognitive performance of improve cognitive performance of elderlyelderly rats rats

25

20

15

10

5

0M

ean

erro

rs p

er tr

ial

BuChEinhibition

(Bisnorcymserine)

Greig et al. 2001

Control

0.25 mg/kg0.5 mg/kg1 mg/kg

Maze

AChE inhibition

(Phenserine)Food

Drug treatments for AD Drug treatments for AD

(Aricept) (Exelon) (Reminyl) (Namenda)

http://content.nejm.org/content/vol351/issue1/images/large/11t1.jpeg

AD: Many patients treated for a AD: Many patients treated for a short time, relative to long-term short time, relative to long-term duration of diseaseduration of disease

AD persists on average AD persists on average for 7–10 years for 7–10 years

In general, patients In general, patients are treated with are treated with cholinesterase (ChE) cholinesterase (ChE) inhibitors inhibitors for only a for only a short duration short duration (e.g.

ChE inhibitors: Different ChE inhibitors: Different pharmacological characteristicspharmacological characteristics

Reversibility Reversible ReversibleVery slowly reversible

CharacteristicDonepezil GalantamineRivastigmine

Enzyme(s) inhibited AChE and BuChE AChE AChE

Sustained ChEinhibition after long-term treatment

Yes No No

Plasma half-life(hours)

1–2 ~70 ~6

nAChR modulation?

No (?) YesNo

Sifton (Physician’s Desk Reference), 2002; Svensson, 1997; Weinstock, 1999; Samochocki et al. 2000 Amici et al. 2001; Davidsson et al. 2001; Darreh-Shori et al. 2002; Parnetti et al. 2002

Potential benefits of inhibiting both Potential benefits of inhibiting both AChE and BuChEAChE and BuChEDual inhibition

Attention, cognition and behaviour

Quality of life

Autonomy

Disease progression?

Improved cholinergic transmission

Possible effect on Aβ

Which translates into broader and more sustained efficacy:

Treatment of Alzheimer’s DiseaseTreatment of Alzheimer’s Disease

Source: Decision Resources, March 2000.

* Any drug treatment, not limited to acetylcholinesterase inhibitors.

0

1

2

3

4

5Pa

tien

ts (millions

)

Prevalence

4,523,100

Diagnosed

2,261,600

Treated*

904,600

Treated with AChEIs

543,800

Dual inhibition of AChE Dual inhibition of AChE and BuChEand BuChE Sustained inhibition of both AChE and BuChE

is correlated with clinical benefit

Additional inhibition of BuChE may have disease-modifying effects

AChE and BuChE inhibition versus AChE-specific inhibition currently being studied

Benefits of Treatment of AD With Benefits of Treatment of AD With Acetylcholinesterase InhibitorsAcetylcholinesterase Inhibitors

AChEIs may improve, maintain, or slow the decline of cognitive, AChEIs may improve, maintain, or slow the decline of cognitive, behavioral, and functional performance in patients with mild-to-behavioral, and functional performance in patients with mild-to-moderate AD.moderate AD.

Delay of treatment leads to loss of potential benefitDelay of treatment leads to loss of potential benefit

AChEIs may delay nursing home placement over 20 months, and AChEIs may delay nursing home placement over 20 months, and potentially much more when started early.potentially much more when started early.

AChEIs have demonstrated consistent efficacy and safety in AChEIs have demonstrated consistent efficacy and safety in maintaining cognitive function, as measured by ADAS-cog in patients maintaining cognitive function, as measured by ADAS-cog in patients with mild-to-moderate AD for up to 1 year – relative to placebo!!with mild-to-moderate AD for up to 1 year – relative to placebo!!

– DonepezilDonepezil11 38 weeks38 weeks– RivastigmineRivastigmine22 38–42 weeks38–42 weeks– GalantamineGalantamine33 52 weeks (25-30% better)52 weeks (25-30% better)

1. Rogers SL et al. Eur Neuropsychopharmacol. 2000;10:195-203. 2. Farlow M et al. Eur Neurol. 2000;44:236-241.3. Raskind MA et al. Neurology. 2000;54:2261-2268.

Selective BuChE inhibition reduces Selective BuChE inhibition reduces APP and Ab levelsAPP and Ab levels

Control PEC 0.5 µM PEC 5 µM PEC 25 µMβ-

APP

leve

ls (%

of c

ontr

ol)

Aβ le

vels

(% o

f con

trol

)PEC=(-)-PhenethylcymserineAPP=amyloid precursor protein

Time (hours)

125

100

75

50

25

0

125

100

75

50

25

0

125

100

75

50

25

0

IntracellularExtracellular

4 8 16 16 8 16

β-A

PP le

vels

(% o

f con

trol

)

Data courtesy of N. Greig

Both AChE and BuChE inhibition reduces Both AChE and BuChE inhibition reduces APP levels in transgenic miceAPP levels in transgenic mice

125

100

75

50

25

0CSF

Control(-)-Phenserine 2.5 mg/kg(-)-Phenethylcymserine 3.0 mg/kg

b-APP

lev

els

in t

rans

genic

mice

(con

trol %

)

*

*

AC

hEI

BuC

hEI

APP Swedish mutation PS1

*p

http://content.nejm.org/content/vol351/issue1/images/large/11t2.jpeg

Exelon Improves Cognitive Function: Exelon Improves Cognitive Function: ADAS-Cog mean change from baselineADAS-Cog mean change from baseline

††M

ean

chan

ge in

ADAS-

Cog

scor

e

Improvement

Worsening

12 18 26 Weeks

***

6–12 mg/day Exelon® 1–4 mg/day Exelon® Placebo

**

†B352 OC study analysis; *p

Exelon Longterm Effects on Cognition:Exelon Longterm Effects on Cognition:Mean Change in ADAS-Cog from Mean Change in ADAS-Cog from Baseline at Week 52Baseline at Week 52

-7-6-5-4-3-2-101

0 10 20 30 40 50 60Study Week

AD

AS-

Cog

Mea

n C

hang

e fr

om B

asel

ine

6-12 mg1-4 mgPlaceboProj. PBO All Patients

Taking Exelon

B352 Patients in B353 (OC) at Week 52

*

*

*

* p< 0.05 vs projected placebo

**

*

*

*

*

Sohn et al. In: Proceedings of the CPNP. April 2000.

Rivastigmine: Long-lasting dual Rivastigmine: Long-lasting dual inhibition of AChE and BuChE in inhibition of AChE and BuChE in patients with ADpatients with AD

Cutler et al. 1998

0.0 2.5 5.0 7.5 10.0 12.5

150

100

50

0

Time (hours)

Rivastigmine 3 mg p.o.

Perc

enta

ge o

f bas

elin

em

ean

± SE

M

AChE in CSF BuChE in CSF

Time (hours)

0.0 2.5 5.0 7.5 10.0 12.5

Rivastigmine 3 mg p.o.

Perc

enta

ge o

f bas

elin

e m

ean

± SE

M

150

100

50

0

CSF–closest available marker to brain

Long-term effects of rivastigmine Long-term effects of rivastigmine on cognition: ADAS-Cogon cognition: ADAS-Cog

Projected placeboRivastigmine 6–12 mg/day PlaceboRivastigmine 1–4 mg/day

0 12 18 26 38 44 52Study week

210

–1–2–3–4–5–6–7–8–9

AD

AS-

Cog

mea

n ch

ange

(±

SEM

) fro

m b

asel

ine

All patients taking rivastigmine 2–12 mg/day

* ****

**

*p

AD drug sales in the USAAD drug sales in the USA

Changes in treatmentChanges in treatment

ChE inhibitors in the management of behavioural symptoms in dementia

‘Cholinesterase Inhibitors: A new class of psychotropic compounds.’ J Cummings – American Journal of Psychiatry 2000;157:4–15

‘‘Cholinesterase inhibitors have psychotropic effects and may Cholinesterase inhibitors have psychotropic effects and may play an important role in controlling neuropsychiatric and play an important role in controlling neuropsychiatric and

behavioral disturbances in patients with Alzheimer’s disease.’behavioral disturbances in patients with Alzheimer’s disease.’

“and in Dementia with Lewy bodies”

15

16

17

18

19

20

21

22

23

Mea

n M

MSE

sco

re ±

SD

Start of donepezil treatment

End of donepezil treatment

Start of rivastigmine

treatment(baseline)

After 16 weeks of

rivastigmine treatment

After 26 weeks of

rivastigmine treatment

3.1-point deterioration

*

n=205*p

Efficacy or tolerability issues with donepezil are Efficacy or tolerability issues with donepezil are not predictive of similar problems with not predictive of similar problems with rivastigminerivastigmine

0

20

40

60

80

100

Response to rivastigmine (GCIC) after lack/loss of efficacy with

donepezil (n=304)

Adapted from Auriacombe et al. 2002

Patie

nts

(%)

Responders

Nonresponders

Tolerability of rivastigmine after safety/tolerability issues with

donepezil (n=78)

0

20

40

60

80

100

Patie

nts

(%)

Well tolerated

Poorly tolerated

Transdermal treatmentTransdermal treatment

– The rivastigmine patch (ExelonThe rivastigmine patch (Exelon®®) is the first ) is the first transdermal treatment for Alzheimer’s diseasetransdermal treatment for Alzheimer’s disease

– The therapeutic dosage of 9,5 mg has a similar The therapeutic dosage of 9,5 mg has a similar effect with the dosage of 12mg and the frequency of effect with the dosage of 12mg and the frequency of nausea and vomiting similiar with the placebo drugnausea and vomiting similiar with the placebo drug

– It is It is easily applied easily applied and does not cause any problems and does not cause any problems while on the skinwhile on the skin

– Καλύτερα ανεκτόΚαλύτερα ανεκτό στους ασθενείς από ότι η θεραπεία στους ασθενείς από ότι η θεραπεία από του στόματοςαπό του στόματος

Body Places for the PatchBody Places for the Patch

V. ALZHEIMER’S DISEASE TREATMENTV. ALZHEIMER’S DISEASE TREATMENT

Non pharmaceuticalNon pharmaceutical– Cognitive, Behavioural, NursingCognitive, Behavioural, Nursing– ΤechnologicalΤechnological

(Global Positioning System, Robots, Wireless audiovisual (Global Positioning System, Robots, Wireless audiovisual networks )networks )

– Training of caregivers, health Training of caregivers, health professionalsprofessionals

Funded AD Prevention and Funded AD Prevention and Selected Treatment TrialsSelected Treatment Trials

Vitamins E, AriceptAspirin, Vitamin E

EstrogenB-Carotene, Vit. E, C

Celecoxib, NaproxenGinkgo Biloba

Vitamin E, SeleniumSimvastatin

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Vitamin E, C, B6, B12, Folate, B-Carotene

April 2002

Ευχαριστώ για την προσοχή σαςΕυχαριστώ για την προσοχή σας

Lesson of Byzantine musicLesson of Byzantine music

Activities of Activities of AD patientsAD patients
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Documents

TREATMENT OF ALZHEIMER’S DISEASETransdermal treatment – The rivastigmine patch (Exelon®) is the first transdermal treatment for Alzheimer’s disease – The therapeutic dosage