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Parkinson’s disease. 1960 - EHRINGER AND HORNYKIEWICZ - DECREASED DOPAMINE CONTENT IN THE SUBSTANTIA NIGRA AND NEOSTRIATUM . The start of levodopa. O. Hornykiewicz and W. Birkmayer . 2006 Prize of Tuscany Association for Neurological Research. DOPAMINE AGONISTS STORY

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slide4

1960 - EHRINGER AND HORNYKIEWICZ - DECREASED DOPAMINECONTENT IN THESUBSTANTIA NIGRAAND NEOSTRIATUM

the start of levodopa
The start of levodopa

O. Hornykiewicz and W. Birkmayer

slide7

DOPAMINE AGONISTS STORY

1951-Schwab :APOMORPHINE i.m. improved PD symptoms

1970-Cotzias :Confirmed APOMORPHINE antiPD effects

1974-Calne:Beneficial effects of BROMOCRIPTINE

in 20 fluctuating PD patients (DB study)

Large use of DA-agonists as add on to levodopain advanced PD

( direct striatal DA-receptors stimulation could overcome the increasing loss of presynaptic nigrostriatal neurons )

‘80s – Rinne,Tolosa,Montastruc :DA-agonist efficacy in early PD

(open/small size studies)

slide9

LIMITATIONS OF CURRENT DOPAMINERGIC PD THERAPY

1. No improvement of non dopaminergic

motor and non motor symptoms

2. Troublesome tardive side effects

Levodopa:motor fluctuations/dyskinesias

DA-agonists:psychosis/somnolence

3. No effects on disease progression (?)

slide10

- PUBMED PAPERS ON:

Dopamine Agonists:

24520 March 2005

26683 March 2007

Dopamine Agonists in PD: 2887 March 2005

3369 March 2007

slide11

Dopamine Agonists in Parkinson Disease-circa 2007

  • Potential/probable neuroprotective effect (presymptomatic diagnosis & treatment?)
  • Well proved symptomatic effect in both early and advanced disease
slide14
Mov Disord 2007 May 31; [Epub ahead of print]

Clinical diagnostic criteria for dementia associated with Parkinson's disease.

    • Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts C, Mizuno Y, Broe GA, Cummings J, Dickson DW, Gauthier S, Goldman J, Goetz C, Korczyn A, Lees A, Levy R, Litvan I, McKeith I, Olanow W, Poewe W, Quinn N, Sampaio C, Tolosa E, Dubois B.
slide15
Mov Disord 2007 Jun 1;

[Epub ahead of print]

Prevalence of nonmotor symptoms in Parkinson's disease in an international setting; Study using nonmotor symptoms questionnaire in 545 patients.

Martinez-Martin P, Schapira AH, Stocchi F, Sethi K, Odin P, Macphee G, Brown RG, Naidu Y, Clayton L, Abe K, Tsuboi Y, Macmahon D, Barone P, Rabey M, Bonuccelli U, Forbes A, Breen K, Tluk S, Olanow CW, Thomas S, Rye D, Hand A, Williams AJ, Ondo W, Chaudhuri KR.

slide16

Neuroprotection:Slowing the progression of neuronal degeneration

Neurorescue:“Normalising” sick neurons which areinjured but not dead

Neurorestoration:Increasing the number of neurons by directly implanting new ones or causing existing cells to divide

degeneration

100

symptoms

Neurorestoration

Dopaminergic neurons (%)

Neurorescue

40

treatment

Neuroprotection

time

etiopathogenesis of parkinson s disease
Etiopathogenesis of Parkinson's disease

Environmental

or endogenous

toxins

Single or

multiple

genes

Pathogenesis

oxidative mitochondrial inflammation excito- UPS dysfunc. apoptosis

stress dysfunction toxicity and protein

aggregation

Parkinson's disease(s)

slide19

Caffeine Adenosine antagonist

Coenzyme Q10Antioxidant/mitoch. enhancer

Creatine Mitoch. enhancer

Estrogen Undetermined/multiple

GPI 1485 Trophic factor

GM-1 ganglioside Trophic factor

Minocycline Anti-inflammatory/anti-apoptotic

Nicotine Unknown

PramipexoleAntioxidant/vesicular trafficking

RopiniroleAntioxidant

RasagilineAntioxidant/anti-apoptotic

Selegiline Antioxidant/anti-apoptotic

preclinical and clinical data suggest neuroprotective effects of dopamine agonists
Preclinical and Clinical Data Suggest Neuroprotective Effectsof Dopamine Agonists
  • Decreased dopamine release and turnover
  • Protection against MPTP and 6-OHDA–induced toxicity
  • Scavenging of free radicals (antioxidant effect)
  • Levodopa-sparing effects
  • SPET & PET studies
putaminal uptake changes of cit and f dopa after da agonists
% Putaminal uptake changes of -CIT and F-Dopa after DA-agonists

%

Reduction from baseline

months

slide24

CLINICAL TRIALS FOR NEUROPROTECTION IN PD

Unsolved questions (1)

1. How to measure neuroprotection? Which outcome?

 clinical rating scales (UPDRS)

 time to clinical endpoints (need to levodopa adjunct, onset of MRC, mortality)

 neuroimaging studies (F-Dopa uptake using PET, DA transporter uptake using SPECT)

2. How to differentiate symptomatic from neuroprotective effects?

 need for an adequate final withdrawal phase

 more proper trial design (ie randomized “start delay”)

3. Recruitment problems: large numbers of drug-naive patients (especially if the magnitude of neuroprotective effect is expected to be small)

slide25

CLINICAL TRIALS FOR NEUROPROTECTION IN PD

Unsolved questions (2)

4. Patient selection (patients with normal baseline radionuclide uptake; “scans without evidence of dopaminergic deficits”, SWEDD)

5. Neuroimaging with radionuclide studies

 is there a clinical correlate?

 rate of decline still controversial

 pharmacodynamic interaction between drug and radioligand uptakes

6. One drug or a combination of drugs in factorial design trials? (“cocktail trials”)

clinical trial new designs for neuroprotection in pd

CLINICAL TRIAL NEW DESIGNSFOR NEUROPROTECTION IN PD

FUTILITY STUDIES

DELAYED START

MULTIPLE CROSSOVER

slide27

New Drugs for PD - FASE II/III

  • NEUROPROTECTIVE
    • MAO B -I Rasagiline(ADAGIO study)
    • Antiapoptotics CEP 134 (interrupted 2004)

TCH 345 (interrupted 2004)

    • Dopamine agonistsPramipexole
    • Neurotrophic Factors GDNF (interrupted 2006)
    • Neuroimmunofillins GPI.1485
slide28

D2-like

D1-like

+/+++ = agonist; - = antagonist; 0 = non active

slide30

Normal

Parkinson’s disease

Frontal cortex

Frontal cortex

- Striatum +

- Striatum +

output

output

D2

D1

D2

D1-D3

GPe

GPe

dopamine

dopamine

direct pathway

direct pathway

indirect pathway

indirect pathway

STN

STN

SNC

SNC

GPi/SNR

GPi/SNR

Thalamus

(VA/VL/MD)

Thalamus

(VA/VL/MD)

GABA

Glutammato

slide31

Dopamine agonist effects on motor cortex:an 1H-MRS study

Lucetti et al. In press 2007

Clinical and demographic data of the populations studied

slide32

A significant improvement in UPDRS subitems II and III was found after 6 months of pergolide therapy. Error bars indicate standard deviation.

slide33

Comparison of metabolite ratios showed lower values of Cho/Cr and NAA/Cr ratios in patients compared with controls.

slide34

A significant increase in Cho/Cr ratios in the motor cortex was observed at the second 1H-MRS compared with the first scan.

slide35

Each spectrum shows the peaks corresponding to the main brain metabolites N-acetylaspartate (NAA), choline (Cho), myo-Inositol (mI), and phosphocreatine/creatine (Cr).

In (a) representing the spectrum from a patient at baseline; in (b) representing the spectrum of the same patient after 6 months of pergolide therapy.

(a)

(b)

dopamine agonists in early pd monotherapy or combination with l dopa
Dopamine Agonists in Early PD(Monotherapy or Combination with l-Dopa)
  • Significantly less motor complications compared to l-Dopa monotherapy

(continuous DA-ergic stimulation ?)

  • About one third remains on agonist monotherapy over 3-5 years

(lose efficacy over time due to advancing disease ?)

  • Symptomatic efficacy of agonist monotherapy slightly less than with L-Dopa (? clinical relevance)
da agonist studies to prevent motor complications methods
DA-agonist Studies to Prevent Motor Complications : Methods

CALM-PD ROP 056 CBG 09 PELMOPET

Dosing of Exp.drug No  after  allowed No  after No  after titration through the study titration titration

Mean Dose DA-ag. 2.87 16.5 2.7 2.5

(mg/day)

Max Dose DA-ag. 4.5 24 4 5

allowed (mg/day)

Mean Am’t Rescue PRA: 264 ROP: 427 CBG: 432 Not allowed

L-dopa (mg/day) L-dopa: 252 L-dopa: 753(tot) L-dopa: 357

Concomitant Allowed at Allowed at Not allowed Not allowed

Anti-PD Drugs unchanged doses unchanged doses

.

rop vs ld in early pd study duration 5 years
268 pts randomizedROP vs LD in early PD study duration: 5 years

RO: #179

LD: #89

53% withdrew the study

49% withdrew the study

#85 (47%)

Study completed

#45 (51%)

Study completed

#29 (16%)

No LD rescue

#56 (31%) add-on LD

#29 (33%)

No LD rescue

#16 (18%) add-on LD

Rascol et al, 2000

slide42

Reappearance of the risk of dyskinesia when levodopa is added to early agonist monotherapy

LD

Rop+LD

Survival analysis of patients remaining free from dyskinesias in the group receiving L-dopa (dotted line) at the start of the trial and in those receiving ropinirole supplemented with L-dopa (solid line; HR, L-dopa/ropinirole, 0.80; 95% CI, 0.48-1.33. Time of starting L-dopa therapy is taken as the time of origin in this figure; therefore, in the ropinirole group, the origin is chronologically later than that in the L-dopa group.Rascol et al. Mov.Dis sept. 2006

dopamine agonists in advanced pd
DOPAMINE AGONISTS in ADVANCED PD

1.Oral DA-agonists

  •  20% (6,5-29) the off time
  •  20% of levodopa daily dose and dyskinesia

2.Apomorphine sc –intermittent

- continuous infusion

continuous dopaminergic stimulation in pd
Continuous Dopaminergic Stimulation in PD

long HL DA-ag > short HL DA-ag

> LD+entacapone > LD alone

LD

Supersensitive

DA receptors

DYSKINESIA

slide48

EARLY & ADVANCED PD: NEW DRUGS

Phase II-III or Registration

DOPAMINERGIC SYSTEM

New levodopa formulations: -Entacapone(approved)

- Melevodopa (approved)

- Duodopa (approved)

MAO-B Inhibitors: - rasagiline (approved)

- safinamide

Dopamine agonists: - rotigotine TDS (submitted)

- lisuride TDS

- ropinirole CR

- SLV-308 [pardoprunox]

slide49

Neurology, 2005

Results

  • reduction of OFF periods
  • no increase of dyskinesia
  • decrease of UPDRS score
  • quality of life improvement
slide50

PREVENTION OF MOTOR COMPLICATIONS

with ENTACAPONE

without ENTACAPONE

STRIDE-PD

Levodopa plasma concentration

0 4 8 12 16

Levodopa dose

Time (h)

associazione da agonisti e l dopa interazione farmacodinamica dati preclinici
ASSOCIAZIONE DA-AGONISTI e L-DOPA: INTERAZIONE FARMACODINAMICAdati preclinici
  • in ratti lesionati con 6-OHDA le concentrazioni striatali di dopamina aumentano notevolmente dopo somministrazione di L-dopa (Watchel e Abercrombie, 1994)
  • La stimolazione dei recettori D2 riporta ad un livello più “fisiologico” il release di dopamina indotto dalla L-dopa (Sarre et al, 1996)
rotigotine chemical formula
Rotigotine Chemical Formula

OH

OH

HO

NH2

N

S

CH3

Dopamine

Rotigotine

several patch sizes can be used to achieve different rates of drug delivery
Several patch sizes can be used to achieve different rates of drug delivery

3rd week30 cm2

13.5 mg*

2nd week20 cm2

9.0 mg*

4th week40 cm2

18.0 mg*

1st week10 cm2

4.5 mg*

* total drug content

slide57
SP 506 − North American ComponentPrimary efficacy endpoint: UPDRS (II&III)change from baseline to end of treatment

Placebo

2

n= 242

1

Neupro®

0

10 cm2

20 cm2

30 cm2

40 cm2

-1

-2

UPDRS II&III

(Mean change in score)

-3

-4

-5

-6

-7

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Week

Washout

Titration

Maintenance

Parkinson Study Group, Arch Neurol 2003; 60: 1721-1728

slide59

2007

updrs

slide60

Neurology, 2007

  • randomized, double-blind, placebo-controlled
  • rotigotine 8 mg/24h (n=120)
  • rotigotine 12 mg/24 h (n=111)
  • placebo (n=120)
  • duration: 24 weeks
  • Primary efficacy measure: daily hour
  • off changes

Significant decrease in mean off time of

1.8 h/d (8 mg group) and 1.2 h/d (12 mg group)

slide61

Efficacy of pramipexole and transdermal rotigotine in advanced Parkinson’s disease: a double-blind, double-dummy, randomised controlled trial

Poewe et al. on behalf of the SP515 InvestigatorsLancet Neurol 6: 513-529, 2007

Patients: Rotigotine, 204; pramipexole, 201; placebo:101; Duration: 36 weeks

Primary efficacy measures: 1. mean absolute change in off time per day from baseline to end of study

2. responder rate (proportion of pts with >30% reduction of off time per day

Mean dose pramipexole: 3.1 mg; Mean dose rotigotine: 12.95 mg/24 h

RESULTS: 1. OFF TIME 2.5 rotigotine 0.9 placebo

2.8 pramipexole

2. RESPONDER RATE: 60% rotigotine 35% placebo

67% pramipexole

advantages of transdermal rotigotine
Advantages of Transdermal Rotigotine
  • Once a day patch delivery
  • Anti-parkinson efficacy in early and late Parkinson’s disease
  • Continuous PK profile (CDS)
    • May prevent motor complications
    • May reduce motor complications
slide66

Neurology 2007

  • -double-blind ontrolled
  • -adjunct to L-dopa therapy
  • ropinirole PR (once-daily):202
  • Placebo:191
  • duration: 24 weeks
  • primary outcome measure: reduction in off daily hours
  • mean ropinirole PR dose: 18.8 mg/d

L-dopa dose reduction in ropinirole PR group: 278 mg/d

% off time, on time, on time with severe dyskinesias

slide68

Advanced PD: NEW THERAPIES Phase II

Dopaminergic & Non-Dopaminergic

Apomorphine (nasal) D1/D2 agonist

Bifeprunox partial D2 agonist; partial 5-HT1A agonist

Talampanel AMPA antagonist

Nebicapone/BIA3202 COMT Inhibitor (phase II completed)

Preladenant/SCH420814 adenosine A2A antagonist

Primavenserin 5-HT2A inverse agonist (for PD psychosis,

dyskinesia reduction observed)

slide69

ADVANCED PD: NEW THERAPIES

Preclinical/Phase I

DOPAMINERGIC SYSTEM

COMT inhibitors: BIA 3202

Dopamine-agonists: - OSU 6162 (partial D2agonist)

- GMC 1111 ( “ “ “ )

- DAR 201 (D1 agonist)

- dinapsoline

- apomorphine TDS

- BP 897 (partial D3 agonist)*

DA reuptake inhibitors: - vanoxerine, BLS065, DOV102677

 DA releaser: AV 201

*for levodopa-induced dyskinesia

comparison among da agonists

COMPARISON AMONG DA-AGONISTS

EFFICACY

&

INDIRECT

DIRECT

SAFETY

d ifferences b etween da agonists in s ide e ffects p rofile
DIFFERENCES BETWEEN DA-agonistsin SIDE-EFFECTS PROFILE

Retroperitoneal & pulmonary fibrosis, Valvulopathy Erythromelalgia

More frequent with ergot derivatives(5-HT2)

Distal and ankle edema

More frequent with non-ergot derivatives

?

More frequent with non-ergot derivatives (D3)

?

Sleep attacks,ICD

c olpi di s onno nella mp studi pubblicati
COLPI DI SONNO NELLA MP: Studi Pubblicati

Da: Homann et al, 2002 (BMJ)

gambling and mp prevalence
Gambling and MP :prevalence

AA year no.pts no.g.(%) drugs

*6.6 DCI;2.6 gambling

slide75

Any ICD

SHOPPING

HIPERSEXUALITY

GAMBLING

ICD and dopaminergic therapy

Voon et al, 2006

details of currently published echocardiography population studies n of patients in brackets

Details of currently published echocardiography population studies(N of patients in brackets)

Antonini and Poewe, Lancet Neurology 2007, in press

slide78

Patients presenting moderate to severe valvulopathy in at least one valve vs. total number of subjects examined (% in brackets). Data on pergolide from studies of Yamamoto et al, and Kim et al are not included as average dose was 1.4 and 1.13 mg/day respectively vs. 3 mg/day in all other studies

Antonini and Poewe, Lancet Neurology 2007, in press

french guidelines for the management of parkinson s disease 2000
French Guidelines for the management of Parkinson’s disease (2000)

Signes Symptômes gêne fonctionelle discrets

Assurer le diagnostic

Age<70 ans

Age>70 ans

Sélégiline

Abstention

VitC/VitE

Sélégiline

+L-dopa (+sélégiline?)

Gêne fonctionelle handicap modérés

Amantadine

Anticholinergiques

<60 ans

>60 ans

+L-dopa

Association “précoce” Agoniste+L-dopa

Agoniste

Gêne handicap sévére

<75 ans

>75 ans

 dose

Substitution

+L-dopa

Agoniste?

 L-dopa

slide82

Review of the therapeutic management of Parkinson’s disease

* Report of a joint task force of EFNS and MDS-European Section

Part I: early (uncomplicated) Parkinson’s disease Part II: late (complicated) Parkinson’s disease

M. Horstink, E. Tolosa, U. Bonuccelli, G. Deuschl, A. Friedman, P. Kanovsky, JP. Larsen, A. Lees, W. Oertel, W. Poewe, O. Rascol, C. Sampaio.

European Handbook of Neurological Management: 2006

Eur J Neurol 2006