Parkinson’s disease

1. Parkinson’s disease

4. 1960 - EHRINGER AND HORNYKIEWICZ - DECREASED DOPAMINECONTENT IN THESUBSTANTIA NIGRAAND NEOSTRIATUM

5. The start of levodopa O. Hornykiewicz and W. Birkmayer

6. 2006 Prize of Tuscany Association for Neurological Research

7. 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)

8. Guidelines of German Neurological Society,2003

9. 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 (?)

10. - PUBMED PAPERS ON: Dopamine Agonists: 24520 March 2005 26683 March 2007 Dopamine Agonists in PD: 2887 March 2005 3369 March 2007

11. Dopamine Agonists in Parkinson Disease-circa 2007 • Potential/probable neuroprotective effect (presymptomatic diagnosis & treatment?) • Well proved symptomatic effect in both early and advanced disease

12. Braak et al.2004

14. 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.

15. 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.

16. 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

17. 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)

18. Committee to Identify Neuroprotective Agents in PD (CINAPS, 2003)

19. 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

20. 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

21. 2007

22. Longitudinal imaging of DAT in PD (-CIT SPECT)

23. % Putaminal uptake changes of -CIT and F-Dopa after DA-agonists % Reduction from baseline months

24. 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)

25. 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”)

26. CLINICAL TRIAL NEW DESIGNSFOR NEUROPROTECTION IN PD FUTILITY STUDIES DELAYED START MULTIPLE CROSSOVER

27. 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

28. D2-like D1-like +/+++ = agonist; - = antagonist; 0 = non active

30. 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

31. Dopamine agonist effects on motor cortex:an 1H-MRS study Lucetti et al. In press 2007 Clinical and demographic data of the populations studied

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

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

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

35. 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)

36. 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)

37. 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 .

38. 268 pts randomized ROP 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

39. ROP 056:Dyskinesia %(regardless of L-dopa rescue) P < 0.0001

40. ROP 056:Mean scores for Motor function (UPDRS part III):P<0.05 L-dopa

41. ROP 056:Mean scores for ADL (UPDRS part II):NS L-dopa

42. 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

43. observed

44. 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

45. Continuous Infusion Minipump Cané

46. APOMORPHINEsc continous infusion in advanced PD: open label studies

47. Continuous Dopaminergic Stimulation in PD long HL DA-ag > short HL DA-ag > LD+entacapone > LD alone LD Supersensitive DA receptors DYSKINESIA

48. 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]

49. Neurology, 2005 Results • reduction of OFF periods • no increase of dyskinesia • decrease of UPDRS score • quality of life improvement

50. PREVENTION OF MOTOR COMPLICATIONS with ENTACAPONE without ENTACAPONE STRIDE-PD Levodopa plasma concentration 0 4 8 12 16 Levodopa dose Time (h)