contents traditional levodopa – strengths traditional levodopa – limitations of pulsatile...

Contents

Traditional levodopa – strengths

Traditional levodopa – limitations of pulsatile delivery

Suboptimal delivery with disease progression

Optimization of levodopa delivery

Stalevo and its benefits

Benefits of earlier optimization of levodopa delivery

Future directions

Conclusions

Treatment with levodopa has dramatically reduced disability and mortality associated with PD

Years since diagnosis

Pat

ien

ts w

ith

sev

ere

dis

abili

ty a

nd

dea

th (

%)

0

20

40

60

80

100

1–5 6–10 11–15

Untreated patients

Levodopa-treated patients

Hoehn and Yahr, 1967;Hoehn, 1983

PD=Parkinson’s disease

Levodopa consistently provides better symptom control compared with dopamine agonists

Improvement with levodopa:

5.9 points vs pramipexole

(p=0.003) on total UPDRS

at 4 years

4.48 points vs ropinirole

(p=0.008) on UPDRS motor

subscale at 5 years

2.9 points vs cabergoline

(p<0.001) on UPDRS motor

subscale at 5 years

Holloway et al, 2004;Rascol et al, 2000;Bracco et al, 2004

Pramipexole

Levodopap=0.003

–4

–2

0

2

40 10 20 30 40 50

Ch

ang

e in

UP

DR

S s

core

–16

–14

–12

–10

–8

–6

0 10 20 30 40 50

Time (months)

Levodopa versus pramipexole

UPDRS=United Parkinson’s Disease Rating Scale

Imp

rove

me

nt

All patients eventually require the superior efficacy of levodopa for symptom control

Need for levodopa in patients initiated with a dopamine agonist (pramipexole)

16%

23%

59%

46%

Pat

ien

ts r

equ

irin

g

sup

ple

men

tal l

evo

do

pa

(%)

0

10

20

30

40

50

60

70

1 2 3 4

PSG, 1997;Holloway et al, 2004

Need for levodopa in patients initiated with a monoamine oxidase inhibitor

(selegiline)

Years after randomization

Pro

bab

ility

of

req

uir

ing

le

vod

op

a th

erap

y (%

)

Months after randomization

60

40

20

0

0 6 12 18 24

Levodopa provides better overall short-term tolerability vs dopamine agonists

Dopaminergic

adverse event

Pergolide vs

levodopa (%)

Pramipexole vs

levodopa (%)

Ropinirole vs

levodopa (%)

Nausea 41 vs 21* 36 vs 37 49 vs 49

Somnolence 10 vs 5 32 vs 17* 27 vs 19

Oedema 5 vs 1* 18 vs 8* 14 vs 6

Hallucinations 3 vs 0* 9 vs 3* 17 vs 6

PSG, 2000;Oertel et al, 2006;

Rascol et al, 2000;Weintraub et al, 2006

Increased incidence of impulse control disorders (e.g. hyperphagia, hypersexuality and gambling) and fibrosis (ergot-derived) have been

associated with dopamine agonist use

* Significantly less with levodopa vs dopamine agonist (p<0.05)

Contents







Future directions

Conclusions

Traditional levodopa therapy is associated with the development of motor complications

Obeso et al, 2000

Early disease• Smooth, long duration of

clinical benefit• Low incidence of

dyskinesias

Mid-stage disease• Diminished duration of

clinical benefit• Increased incidence of

dyskinesias

Advanced disease• Clinical response mirrors

levodopa plasma pharmacokinetic profile

• ‘On’ time is associated with dyskinesias

Time (hours)

Levodopa2 4 6

Cli

nic

al

eff

ec

t

Levodopa2 4 6

Cli

nic

al

eff

ec

t

Levodopa2 4 6

Cli

nic

al

eff

ec

t

On

Off

Response threshold

Dyskinesia threshold

In PD, traditional levodopa delivery leads to pulsatile dopamine levels in the brain

The short half-life (60–90 min) of traditional

levodopa leads to peaks and profound troughs in plasma levodopa levels which are

further worsened by intermittent dosing

Pulsatile plasma levodopa levels leads to pulsatile levels of dopamine in the brain

In PD, the ability to regulate and maintain

steady levels of dopamine in the brain is

reduced due to progressing neuronal

loss

The first manifestation of pulsatile levodopa delivery in the brain is often wearing-off

Pulsatile levels of dopamine in the brain translate into fluctuations in clinical

response

Often the first complaint patients have is that the duration of symptom control

provided by their traditional levodopa becomes shorter (‘wears-off’) and their

symptoms re-emerge before the next scheduled dose

Traditional levodopa

TimeSymptom

re-emergence

Symptoms controlled

Stacy et al, 2005

The long-term consequence of pulsatile levodopa delivery in the brain is often dyskinesia

In PD, pulsatile plasma levodopa levels translates into pulsatile levels of dopamine in the brain

Pulsatile stimulation of striatal dopamine receptors

Further destabilization of an already unstable basal ganglia

Dyskinesia

Contents







Future directions

Conclusions

Constant levels of dopamine are vital for normal movement

In the brain, constant levels

of dopamine are required to

Regulate cortical excitation

of striatal neurons

Stabilize the firing rate and

excitability of striatal

neurons

Modulate plasticity of striatal

neurons (long-term

potentiation)

Olanow et al, 2006

Striatum

Substantia nigra

Excitatory cortical input

Normal motor function

Dopaminergic

regulatory input

Basal ganglia

In PD, pulsatile delivery of traditional levodopa leads to pulsatile stimulation of dopamine receptors


Activated

Unactivated

Normal

PD (untreated)


Substantia nigra

Striatum

Dopamine receptor state

Nigrostriatal neuronsdegenerate

Activated

Unactivated

Activated

Unactivated

In PD, pulsatile delivery of traditional levodopa leads to pulsatile stimulation of the dopamine receptors

Olanow et al, 2006

Normal Movement

Parkinsonian State

Parkinsonian State with Intermittent Levodopa

Parkinsonian State with Continuous Levodopa

In PD patients with motor complications, fluctuations in brain dopamine levels correspond to levels of levodopa

Baseline 1 hourafter oral levodopa

4 hoursafter oral levodopa

De la Fuente-Fernández et al, 2001

Pu

tam

en r

aclo

pri

de

bin

din

g p

ote

nti

al(r

esp

on

se t

o le

vod

op

a)

Incr

easi

ng

syn

apti

c d

op

amin

e le

vels

In PD, pulsatile stimulation causes further changes in gene expression in the already unstable basal ganglia

Pre-proenkephalin B (marker for dyskinesia) mRNA expression in the caudate-putamen

Henry et al, 2003

Non-parkinsonian patient PD patient with dyskinesia

Pulsatile stimulation leads to gene changes in the basal ganglia of MPTP primates whereas continuous stimulation does not

Normal Pulsatile stimulation Continuous stimulation

Pre-proenkephalin-B (PPE-B; marker for dyskinesia) mRNA expression in the striatum

High

Low

Reproduced with permission from Peter Jenner

Contents



Suboptimal levodopa delivery with disease progression




The patient’s perspective

Conclusions

Oral levodopaAfter 6 months’ levodopa infusion

Pla

sma

levo

do

pa

con

cen

trat

ion

(n

g/m

l)Continuous delivery of levodopa by infusion reverses motor complications

Stocchi et al, 2005

p<0.001

0

1

2

3

4

5

6

7

8

9

Off-time (h/day)

Dyskinesia score (AIMS)

p<0.001

AIMS=Abnormal Involuntary Movement Score

0

1000

2000

3000

4000

5000

09.00 11.00 13.00 15.00 17.00 19.00

Time of day

But infusion is impractical

Avoiding deep troughs in levodopa plasma levels may be more important than providing smooth delivery

Pharmacokinetic analysis of levodopa infusion versus traditional

oral therapy found:

Significantly higher trough levels (Cmin), bioavailability (area under

the curve) and plasma concentrations with infusion

No significant differences in plasma variability (Cmax – Cmin)

Therefore, maintaining completely smooth plasma levodopa

levels may not be as important as avoidance of deep trough

levels (minimum threshold level)

Stocchi et al, 2005

Increasing traditional levodopa dose frequency does not address pulsatility

0

500

1000

1500

2000

2500

3000

8 10 12 14 16 18 20Lev

od

op

a p

lasm

a le

vels

(n

g/m

l)

Levodopa administration

0

500

1000

1500

2000

2500

3000

7 9 11 13 15 17 19 21

5-hour intervals 3-hour intervals

Trough

TroughTrough

Time of day

Stocchi, 2006

Adherence is an important issue in PD and may contribute to pulsatile stimulation

% p

atie

nt

com

plia

nce

wit

h

levo

do

pa

reg

imen

“Poor timing compliance was universal… suggesting that erratic

drug-taking is the norm rather than the exception in PD”

“Given the significance attached to pulsatile stimulation of dopamine receptors… this

suggests that irregular medication maybe... as significant as variable absorption in day-

to-day and longer-term fluctuations”

Grosset et al, 2005

Timing of medication

Total Daily

100

80

60

40

20

0

Therefore, increasing the frequency of traditional levodopa dosing leads to variable control and increased risk of peak dose dyskinesia

Decrease interdose interval

May work in earlier stages

Variable/short-term control

Increase dosing frequency

Limited utility and complicated dosing schedule beyond five

doses per day

‘On’ dyskinesias

Traditionallevodopa

Therapeuticwindow

‘Wearing-off’

Lev

od

op

a p

lasm

a co

nce

ntr

atio

ns

(ng

/ml)

1 3 5 7 9 11 13 Time (h)

Stocchi, 2006

Increasing the dose of traditional levodopa does not prevent pulsatility

Stocchi et al, 2004

0

500

1000

1500

07.00 09.00 11.00 13.00 15.00

100 mg levodopa

Trough Trough

Lev

od

op

a p

lasm

a le

vels

(n

g/m

l)

Time of day

100 mg; 3-hour intervals 150 mg; 3-hour intervals

150 mg levodopa

0

500

1000

1500

07.00 09.00 11.00 13.00 15.00

Trough Trough

Therefore increasing the dose of traditional levodopa leads to variable control

Increase dose

Peak–dose dyskinesias


Higher peakconcentrations

Traditionallevodopa

Therapeuticwindow

‘Wearing-off’

Peak–dosedyskinesias

Lev

od

op

a p

lasm

a co

nce

ntr

atio

ns

(ng

/ml)

1 3 5 7 9 11 13 Time (h)

Stocchi, 2006

Controlled-release levodopa does not prevent pulsatility or motor complications

200 mg

Time of day19.0017.0015.0013.0011.0009.0007.00

2500

2000

1500

1000

500

0Lev

od

op

a p

lasm

a le

vels

(n

g/m

l)

Delayed ‘on’ due to erratic absorption

Stocchi, 2006;Figure adapted from Koller et al, 1999

% p

atie

nts

wit

h m

oto

r co

mp

lica

tio

ns

20

15

10

5

0

0 1 2 3 4 5Year


Controlled-release levodopa

Trough

Controlled-releaseformulations

Delayed ‘on’ or occasional lack of ‘on’ response with

advancing disease


Unpredictabledrug absorption

Therefore, use of controlled-release formulations leads to unpredictable absorption and variable control

‘On’dyskinesias

Traditionallevodopa

Therapeuticwindow

‘Wearing-off’

Lev

od

op

a p

lasm

a co

nce

ntr

atio

ns

(ng

/ml)

1 3 5 7 9 11 13 Time (h)

Stocchi, 2006

Fariello, 1998

Dopamine agonists do not alter the pharmacokinetic profile of levodopa

Pla

sma

con

cen

trat

ion

so

f le

vod

op

a (m

g/l

)

Time (min)

1.2

0.0

0.2

0.4

0.6

0.8

1.0

0 60 120 180 240 300 360 420 480

LevodopaLevodopa + cabergoline

How can we mimic infusion with oral therapy?

Contents







The patient’s perspective

Conclusions

Gordin et al, 2004

Compared with traditional levodopa, Stalevo has a longer levodopa plasma half-life with increased levodopa uptake to the brain

DDC=dopa decarboxylaseCOMT=catechol-O-methyltransferase

Stalevo enhances the pharmacokinetics of levodopa


Time by which the half-life of levodopa

is extended

0

0.5

1.0

1.5

2.0

2.5

0 0.5 1 2 3 4

Time (h)

Pla

sma

levo

do

pa

(µg

/ml)

Stalevo

Gordin et al, 2004

Dual DDC/COMT inhibition increases levodopa uptake into the brain

Sawle et al, 1994

DDC=dopa decarboxylaseCOMT=catechol-O-methyltransferase

Carbidopa Carbidopa/entacapone

Stalevo delivery mimics infusion

08.00 10.00 12.00 14.00 16.00 18.00 20.000

1000

2000

3000

4000

5000

Stocchi et al, 2005;Stocchi, 2006

0

1000

2000

3000

4000

5000

09.00 11.00 13.00 15.00 17.00 19.00

Pla

sma

levo

do

pa

con

cen

trat

ion

(n

g/m

l)

Time of day

Traditional levodopaAfter 6 months’ levodopa infusion

Traditional levodopaStalevo

ONOFF

* 200 mg †100mg

* † † † †

Immediate benefits versus traditional levodopa: more time without symptoms

Stalevo/LCE Traditional levodopa plus placebo

Ch

ang

e in

dai

ly ‘

on

’ ti

me

(h)

·

····

·

p<0.001p<0.001

B 2 4 8 16 24 Withdrawal

Time (weeks)

–0.5

0

0.5

1.0

1.5

2.0

Rinne et al, 1998

Mean daily time without symptoms (‘on’ time) increased by up to 1.7 hours versus baseline

Immediate benefits versus traditional levodopa: improved motor scores

Rinne et al, 1998

–4

–3

–2

–1

0

1

2

3

4

5

Traditional levodopa plus placebo

Stalevo/LCE

Cha

nge

in m

otor

sco

res

Wo

rsen

ing

Imp

rove

me

nt

p<0.05

Immediate benefits versus traditional levodopa: improved quality of life

MDSCRTG and QUEST-AP study group, 2006

StalevoTraditional levodopa

PDQ-8: Parkinson’s Disease Questionnaire, 8 item

-0.1

-0.3

-0.2

0.0

0.1

0.2

0.3

Wo

rsen

ing

Imp

rove

me

nt

Mea

n c

han

ge

in P

DQ

-8 s

core

at

wee

k 12

Q1 Q2 Q3 Q4 Q6 Q7 Q8Q5

Q1. Had difficulty gettingaround in public?

Q2. Had difficulty dressing?

Q3. Felt depressed?

Q4. Had problems with close personal relationships?

Q5. Felt unable to concentrate?

Q6. Felt unable to communicate?

Q7. Had painful muscle cramps or spasms?

Q8. Felt embarrassed?

p=0.056 p=0.025

p=0.037 p=0.007

p=0.033

NS

NS NS

Immediate benefits vs traditional levodopa in stable patients

Stalevo/LCE provides:

Improvements in activities of daily

living (ADL) scores of 0.9–2.2 points

versus traditional levodopa

US-01 study: significant improvements

in QoL versus traditional levodopa

PDQ-39 Total Score (P=<0.001)

SF-36 Physical Component Score

(P=0.009)

Poewe et al 2002; Brooks et al 2003;Olanow et al 2004

Stalevo/LCE

Levodopa/DDCI plus placebo

-0.5

-1.5

-1

0

0.5

1

1.5

2 Celomen UK–Irish

Wo

rsen

ing

Imp

rove

me

nt

AD

L S

core

Long-term benefits: sustained patient function for at least 3 years

UP

DR

S

Larsen et al, 2003

40.8

10.5

28.4

41.7

10.8

29.0

0

5

10

15

20

25

30

35

40

45

Total score ADLscore

Motor score

Baseline

After 3 years Stalevo/LCE

Long-term benefits: sustained efficacy versus baseline for at least 5 years

Nissinen et al, 2006

Ch

ang

e fr

om

bas

elin

e in

du

rati

on

o

f b

enef

it o

f m

orn

ing

do

se (

hrs

)

0

1

B 3 6 9 12 16 20 24 28 32 36 40 44 48 52 56

Month

Stalevo/LCE

Long-term benefits: no need to increase the levodopa dose for at least 3 years

400

600

800

1000

0 6 18 42

Months

Lev

od

op

a d

ose

(m

g)

Double-blind(NOMECOMT)

Open-label(NOMESAFE)

Washout

Larsen et al, 2003

Stalevo/LCE

Stalevo/LCE and its benefits

Immediate benefitsMore time without symptoms

Mean daily ‘on’ time increased by up to 1.7 hours

Better patient functionMean ADL scores improved by up to 1.7 pointsMean motor scores improved by up to 3.2 pointsSignificant improvements in QoL domains

Long-term benefitsSustained patient function through 5 yearsNo need to increase the levodopa dose for at least 3 years

Parkinson Study Group, 1997; Myllyla et al, 2001; Poewe et al, 2002;Rinne et al, 1998;

Brooks et al, 2003; Larsen et al, 2003;


Stalevo provides significantly improved QoL compared with standard of care

The cost-effectiveness of

Stalevo was compared with UK

standard of care

Patients on Stalevo had

significantly improved QoL

(+1.04 QALYs)

The costs to society decreased

by £10,200/patient/10 years

This decrease was mainly due

to savings in social service

costs and secondary care

Societal perspective

Cost (£) QALYs

Stalevo 59,563 2.571

Standard of care 69,761 1.529

Difference:

Stalevo standard of

care

10,198 1.042

Findley et al, 2005QUALY: quality-adjusted life-years

Contents







Future directions

Conclusions

Patients can require optimization of traditional levodopa therapy within only 6 months

In the ELLDOPA study, patients initiated with traditional

levodopa (150–600 mg) experienced:

Wearing-off (16–30%)

Dyskinesia (3–17%)

The time of onset for these complications was only 5–6 months

after initiation of traditional levodopa therapy

Fahn et al, 2004;Fahn, 2005

In de novo disease, early initiation of effective therapy provides long-term benefits versus no treatment

“We suggest that early restoration of basal ganglia physiology will support the compensatory events and delay the irreversible modification of circuitry that characterizes the clinical progression of PD”

Schapira and Obeso 2006

Fahn et al, 2004; PSG, 2004; Schapira and Obeso 2005

Levodopa

Ch

ang

e in

to

tal U

PD

RS

sco

re (

un

its)

Weekof study drug

Baseline

2 6 10 14 18 22 26 30 34 38 42 46

12

10

8

6

4

2

0

–2

–4

–6

–8

Placebo

150 mg

300 mg

600 mg

Withdrawal

2 6 10 14 18 22 26 30 34 38 42 46

12

10

8

6

4

2

0

–2

–4

–6

–8

Placebo

150 mg

300 mg

600 mg

Years

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0

0

10

20

30

40

50

60

70

80

90

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0

0

10

20

30

40

50

60

70

80

90

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.00.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.00.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0

0

10

20

30

40

50

60

70

80

90

0

10

20

30

40

50

60

70

80

90

0

10

20

30

40

50

60

70

80

90

Delayed start

Early start*

* *

*

*

*

NS

NS

NS NS

NS

NS

(n=404) (n=324) (n=272) (n=237) (n=206) (n=164)

Mea

n %

ch

ang

e in

to

tal U

PD

RS Rasagiline

Starting Stalevo/LCE earlier provides superior motor scores at 1 year

• At 1 year, early initiation of Stalevo/LCE provided significantly better motor

function compared with a 6-month delay (treatment difference –1.33 points,

p<0.05)

–4.0

–2.0

0.0

2.0

Baseline (n=484)

3 (n=476)

6 (n=479)

9 (n=445)

12 (n=410)

Months

Ch

ang

e in

UP

DR

S II

I sco

res

Stalevo/LCETraditional levodopa plus placebo


Imp

rove

me

nt

The benefit of starting Stalevo/LCE earlier is sustained over 5 years

The significant difference in UPDRS III scores between the early and delayed start groups

was maintained through the study period

This suggests that optimizing levodopa therapy earlier, even by 6 months

(e.g. only one office visit), can have clinically significant long-term benefits

–6.0

0.0

6.0

12.0

18.0

Baseline(n=484)

1(n=410)

2(n=101)

3 (n=90)

4 (n=44)

5 (n=37)

Years

Ch

ang

e in

UP

DR

S II

I sco

res

Stalevo/LCETraditional levodopa plus placebo


Imp

rove

me

nt

Contents







Future directions

Conclusions

The MPTP primate model of PD has been very predictive of clinical outcomes in idiopathic PD

Years

Su

rviv

al d

istr

ibu

tio

n

fun

ctio

n

0.0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4 5

RopiniroleTraditional levodopa

Dys

kin

esia

sco

re

Days

MPTP model Idiopathic PD

0

1

2

3

4

1 8 15 22

Rascol et al, 2000; Maratos et al, 2001 MPTP: 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine

Studies in MPTP primates show the potential of early initiation of Stalevo/LCE to avoid dyskinesia induction

Studies conducted in the MPTP-

treated primate model of PD

Compared with traditional levodopa,

Stalevo/LCE (4x/day)

Significantly improves the

antiparkinsonian response

Significantly decreases in intensity

and duration of peak dyskinesia

†p<0.05

† †Pea

k d

yski

nes

ia

Smith et al, 2005

0

1

2

3

4

1 4 7 10 13 16

Stalevo/LCE (4x/day)

Traditional levodopa (4x/day)

0

25

50

100

10

% n

igra

l neu

ron

s re

mai

nin

g

0

1

2

3

4

Pea

k d

yski

nes

iaTrad

levodopa Stalevo/LCE

90% MPTP-induced lesion

0

1

2

3

4

Pea

k d

yski

nes

ia

Tradlevodopa

4x/day dosing

Stalevo/LCE

50% MPTP-induced lesion 75% MPTP-induced lesion

0

1

2

3

4

Pea

k d

yski

nes

ia

Tradlevodopa

Stalevo/LCE

Stalevo/LCE has a lower risk of dyskinesia induction versus traditional levodopa, regardless of parkinsonian severity in the MPTP primate model of PD

p<0.05

4x/day dosing

4x/day dosing

Jenner et al, 2006

STRIDE-PD: an ongoing clinical study to confirm the potential of Stalevo to avoid dyskinesia induction

Aim:

To demonstrate that when used as initial levodopa therapy*,

Stalevo results in a significant prolongation in the time to onset

of dyskinesia when compared with traditional formulation

levodopa/carbidopa in PD

With comparable symptom control

With similar QoL

*De novo use of Stalevo is not currently licensedOlanow, 2006

FIRST-STEP: an ongoing clinical study to confirm the efficacy of Stalevo in de novo disease

Aim:

To evaluate the effect of Stalevo 100 (3x/day) versus traditional

formulation levodopa/carbidopa 100/25 mg (3x/day) in PD

patients requiring levodopa therapy

Hauser, 2006

Contents







Future directions

Conclusions

Conclusions I

Compared with other antiparkinsonian therapies, levodopa has superior efficacy and short-term tolerability

However, traditional levodopa therapy is often spared due to concerns about the development of motor complications

The pulsatile stimulation of dopamine receptors caused by traditional levodopa is an important factor in the development of these complications

Infusion data show that consistent delivery of levodopa reverses established complications, even though high doses are used

Modification strategies fail to address the pulsatility of traditional levodopa and therefore frequent changes are often required

Conclusions II

Stalevo provides oral levodopa in a manner which closely

mimics infusion

In fluctuating patients, optimization of levodopa delivery with

Stalevo significantly improves patient function

This benefit is sustained for at least 5 years without the need to

increase the levodopa dose

Initiating Stalevo 6 months earlier may lead to long-term

benefits in patient function

Bibliography

Bracco, F., Battaglia A., Chouza C. et al. The long-acting dopamine receptor agonist cabergoline in early Parkinson's disease: final results of a 5-year, double-blind, levodopa-controlled study. CNS Drugs 2004; 18(11): 733–746.

Hoehn, M. M. and Yahr M. D. Parkinsonism: onset, progression, and mortality. Neurology 1967; 17(5): 427–442.

Hoehn, M. M. and Elton R. L. Low dosages of bromocriptine added to levodopa in Parkinson's disease. Neurology 1985; 35(2): 199–206.

Hoehn, M. M. The natural history of Parkinson's disease in the pre-levodopa and post-levodopa eras. Neurol Clin 1992; 10(2): 331–339.

Holloway, R. G., Shoulson I., Fahn S. et al. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch Neurol 2004; 61(7): 1044–1053.

Oertel, W. H., Wolters E., Sampaio C. et al. Pergolide versus levodopa monotherapy in early Parkinson's disease patients: The PELMOPET study. Mov Disord 2006; 21(3): 343–353.

Traditional levodopa – strengths I

Olanow, C. W., Y. Agid, Y. Mizuno et al. Levodopa in the treatment of Parkinson's disease: current controversies. Mov Disord 2004a; 19(9): 997–1005.

Parkinson Study Group. Safety and efficacy of pramipexole in early Parkinson disease. A randomized dose-ranging study. JAMA 1997a; 278(2): 125–130.

Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. JAMA 2000; 284(15): 1931–1938.

Poewe, W. H. and G. K. Wenning. The natural history of Parkinson's disease. Neurology 1996; 47(6 Suppl 3): S146–152.

Rascol, O., Brooks D. J., Korczyn A. D. et al. (056 Study Group). A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa. N Engl J Med 2000; 342(20): 1484–1491.

Weintraub, D., Siderowf A. D., Potenza M. N. et al. Association of dopamine agonist use with impulse control disorders in Parkinson’s disease. Arch Neurol 2006; 63(7): 969–973.

Traditional levodopa – strengths II

Obeso, J. A., Rodriguez-Oroz M. C., Chana P. et al. The evolution and

origin of motor complications in Parkinson's disease. Neurology 2000;

55(11 Suppl 4): S13–S20.

Olanow, C. W., Obeso J. A. and Stocchi F. Continuous dopamine-

receptor treatment of Parkinson's disease: scientific rationale and

clinical implications. Lancet Neurol 2006; 5(8): 677–687.

Stacy, M., Bowron A., Guttman M. et al. Identification of motor and

nonmotor wearing-off in Parkinson's disease: comparison of a patient

questionnaire versus a clinician assessment. Mov Disord 2005; 20(6):

726–733.


de la Fuente-Fernandez, R., Lu J. Q., Sossi V. et al. Biochemical variations in the synaptic level of dopamine precede motor fluctuations in Parkinson's disease: PET evidence of increased dopamine turnover. Ann Neurol 2001; 49(3): 298–303.

Henry, B., Duty S., Fox S. H. et al. Increased striatal pre-proenkephalin B expression is associated with dyskinesia in Parkinson's disease. Exp Neurol 2003; 183(2): 458–468.

Olanow, C. W., Obeso J. A. and Stocchi F. Continuous dopamine-receptor treatment of Parkinson's disease: scientific rationale and clinical implications. Lancet Neurol 2006; 5(8): 677–687.

Sub-optimal delivery with disease progression

Optimization of levodopa delivery I

Fariello, R. G. Pharmacodynamic and pharmacokinetic features of cabergoline. Rationale for use in Parkinson's disease. Drugs 1998; 55 (Suppl 1): 10–16.

Grosset, K. A., Bone I. and Grosset D. G.. Suboptimal medication adherence in Parkinson's disease. Mov Disord 2005; 20(11): 1502–1507.

Koller, W. C., Hutton J. T., Tolosa E. et al. Immediate-release and controlled-release carbidopa/levodopa in PD: a 5-year randomized multicenter study. Carbidopa/Levodopa Study Group. Neurology 1999; 53(5): 1012–1019.

National Institute for Clinical Excellence (2006). NICE clinical guideline: Parkinson's disease: diagnosis and management in primary and secondary care. http://guidance.nice.org.uk/CG35 Last accessed March 2007.

Nyholm, D., Lennernas H., Gomes-Trolin C. et al. Levodopa pharmacokinetics and motor performance during activities of daily living in patients with Parkinson's disease on individual drug combinations. Clin Neuropharmacol 2002; 25(2): 89–96.

Stocchi, F., Battaglia G., Vacca L. et al. Clinical models of continuous dopaminergic stimulation. Movement Disorders 2004; 19(Suppl 9): S435.

Stocchi, F., Vacca L., Ruggieri S. et al. Intermittent vs continuous levodopa administration in patients with advanced Parkinson disease: a clinical and pharmacokinetic study. Arch Neurol 2005; 62(6): 905–910.

Stocchi, F. The levodopa wearing-off phenomenon in Parkinson's disease: pharmacokinetic considerations. Expert Opin Pharmacother 2006; 7(10): 1399–1407.

Optimization of levodopa delivery II

Stalevo and its benefits I

Brooks, D. J. and Sagar H. Entacapone is beneficial in both fluctuating and non-fluctuating patients with Parkinson's disease: a randomised, placebo controlled, double blind, six month study. J Neurol Neurosurg Psychiatry 2003; 74(8): 1071–1079.

Findley, L. J., Lees A., Apajasalo M. et al. Cost-effectiveness of levodopa/carbidopa/entacapone (Stalevo) compared to standard care in UK Parkinson's disease patients with wearing-off. Curr Med Res Opin 2005; 21(7): 1005–1014.

Goetz, C. G., Stebbins G. T. and Blasucci L. M. Differential progression of motor impairment in levodopa-treated Parkinson's disease. Mov Disord 2000; 15(3): 479–484.

Gordin, A., Kaakkola S. and Teravainen H. Clinical advantages of COMT inhibition with entacapone - a review. J Neural Transm 2004; 111(10–11): 1343–1363.

Stalevo and its benefits II

Larsen, J. P., Worm-Petersen J., Siden A. et al. The tolerability and efficacy of entacapone over 3 years in patients with Parkinson's disease. Eur J Neurol 2003; 10(2): 137–146.

Movement Disorder Society of Australia Clinical Research and Trial Group and QUEST-AP study group. A randomized, double-blind study to compare the effect on quality of life of levodopa/carbidopa/entacapone (Stalevo®) with levodopa/carbidopa in patients with Parkinson’s disease with no or minimal, nondisabling motor fluctuations. Mov Disord, 2006; 21(Suppl 15): S446.

Muller, T., Erdmann C., Muhlack S. et al. Inhibition of catechol-O-methyltransferase contributes to more stable levodopa plasma levels. Mov Disord 2006; 21(3): 332–336.

Myllyla, V., Kultalahti E. R. V., Haapaniemi H. et al. Twelve-month safety of entacapone in patients with Parkinson's disease. Eur J Neurol 2001; 8(1): 53–60.

Stalevo and its benefits III

Nissinen, H., Kuoppamaki M. and Leinonen M.. Early initiation of entacapone leads to superior 5-year efficacy compared to delayed initiation in Parkinson’s disease patients receiving traditional levodopa/DDCI therapy. Mov Disord, 2006; 12(Suppl 15): S593.

Olanow, C. W., Kieburtz K., Stern M. et al. Double-blind, placebo-controlled study of entacapone in levodopa-treated patients with stable Parkinson disease. Arch Neurol 2004b; 61(10): 1563–1568.

Poewe, W. The role of COMT inhibition in the treatment of Parkinson's disease. Neurology 2004; 62(1 Suppl 1): S31–S38.

Poewe, W. H., Deuschl G., Gordin A. et al. Efficacy and safety of entacapone in Parkinson's disease patients with suboptimal levodopa response: a 6-month randomized placebo-controlled double-blind study in Germany and Austria (Celomen study). Acta Neurol Scand 2002; 105(4): 245–255.

Stalevo and its benefits IV

Parkinson Study Group. Entacapone improves motor fluctuations in levodopa-treated Parkinson's disease patients. Ann Neurol 1997b; 42(5): 747–755.

Rinne, U. K., Larsen J. P., Siden A. et al. Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations. Nomecomt Study Group. Neurology 1998; 51(5): 1309–1314.

Sawle, G. V., Burn D. J., Morrish P. K. et al. The effect of entacapone (OR-611) on brain [18F]-6-L-fluorodopa metabolism: implications for levodopa therapy of Parkinson's disease. Neurology 1994; 44(7): 1292–1297.

Stocchi, F. The levodopa wearing-off phenomenon in Parkinson's disease: pharmacokinetic considerations. Expert Opin Pharmacother 2006; 7(10): 1399–1407.

Stocchi, F., Vacca L., Ruggieri S. et al. Intermittent vs continuous levodopa administration in patients with advanced Parkinson disease: a clinical and pharmacokinetic study. Arch Neurol 2005; 62(6): 905–910.

Fahn, S. Does levodopa slow or hasten the rate of progression of Parkinson's disease? J Neurol 2005; 252(Suppl 4): iv37–iv42.

Fahn, S., Oakes D., Shoulson I. et al. Levodopa and the progression of Parkinson's disease. N Engl J Med 2004; 351(24): 2498–2508.

Nissinen, H., Kuoppamaki M. and Leinonen M. Early initiation of entacapone leads to superior 5-year efficacy compared to delayed initiation in Parkinson’s disease patients receiving traditional levodopa/DDCI therapy. Mov Disord 2006; 21(Suppl13): S111.

Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol 2004; 61(4): 561–566.

Schapira, A. H. and Obeso J. Timing of treatment initiation in Parkinson's disease: a need for reappraisal? Ann Neurol 2006; 59(3): 559–562.


Hauser, R. The First-step study: a study to evaluate the effects of intitiating a fixed dose of Stalevo or levodopa/carbidopa t.i.d. in early PD patients requiring levodopa. Eur J Neurol 2006; 13(Suppl 2): 94.

Jenner, P., Jackson M., Rose S. et al. Coadministration of levodopa/carbidopa/entacapone avoids dyskinesia induction in MPTP-treated primates with full or partial nigral lesions. Mov Disord 2006; 21 (Suppl 13): S73.

Maratos, E. C., Jackson M. J., Pearce R. K. et al. Antiparkinsonian activity and dyskinesia risk of ropinirole and L-DOPA combination therapy in drug naive MPTP-lesioned common marmosets (Callithrix jacchus). Mov Disord 2001; 16(4): 631–641.

Future directions I

Olanow, C. W. The STRIDE-PD (Stalevo Reduction In Dyskinesia Evaluation) Study: A Long-term, Controlled study to evaluate the effects of initiating Stalevo or carbidopa/levodopa in early PD. Eur J Neurol 2006; 13(Suppl 2): 93.

Rascol, O., Brooks D. J., Korczyn A. D. et al. A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 2000; 342(20): 1484–1491.

Smith, L. A., Jackson M. J., Al-Barghouthy G. et al. Multiple small doses of levodopa plus entacapone produce continuous dopaminergic stimulation and reduce dyskinesia induction in MPTP-treated drug-naive primates. Mov Disord 2005; 20(3): 306–14.

Future directions II

contents traditional levodopa – strengths traditional levodopa – limitations of pulsatile...

Documents

supplemental levodopa

traditional levodopa

parkinsons disease levodopa

superior efficacy of

pulsatile dopamine levels

pulsatile levels of

steady levels of dopamine

dopamine agonistsimprovement