1. Considering the pre-clinical and clinical evidence for continuous dopaminergic stimulation (CDS) This educational material has been supported by Abbott

2. Considering the pre-clinical and clinical evidence for continuous dopaminergic stimulation (CDS) Potential of CDS for the management of motor symptoms in early and advanced Parkinson’s disease >

3. Learning objectives At the end of this section you will: Have gained knowledge of the potential advantages of continuous dopaminergic stimulation (CDS) in early and advanced Parkinson’s disease Know the clinical evidence supporting long-term CDS

4. Continuous dopaminergic stimulation: Principal hypothesis Evidence suggests that pulsatile drug delivery and receptor stimulation are involved in the emergence of motor complications in Parkinson’s disease, and that CDS may prevent motor complications and ameliorate or reverse them once established in advanced disease Mouradian M. European Neurological Disease 2006:4:62-7.

5. Acute efficacy of continuous levodopa delivery Chapter 1: The continuous dopaminergic stimulation concept and evidence to date. M Maral Mouradian. From: Managing Advanced Parkinson’s Disease: The role of continuous dopaminergic stimulation. Aquilonius and Lees (Ed). 2007.

6. Continuous dopaminergic treatment widens the therapeutic window Baronti F, et al. Continuous lisuride effects on central dopaminergic mechanisms in Parkinson's disease. Annals of Neurology Vol, 32, No. 6, 1992, p776-81. Copyright (2007 Arthritis and Rheumatism); Reproduced with permission of John Wiley & Sons, Inc.

7. Long-term CDS reverses pulsatile levodopa-induced changes Juncos JL, Mouradian MM, Fabbrini G, Chase TN. Levodopa infusion therapy. In Koller WC, Paulson, G (Eds). Therapy of Parkinson's disease. Marcel Dekker, New York, p185-203. ©1990 Reproduced with permission of Taylor & Francis, Inc.

8. Rationale for CDS in early and advanced Parkinson’s disease Early CDS at the outset of anti-Parkinson’s disease treatment could delay or prevent the onset of motor complications Advanced CDS can reverse the motor complications already evident in patients with advanced Parkinson’s disease

9. Potential for CDS in early disease: Clinical evidence Dopamine agonists vs levodopa: 29 studies, 5247 patients Adapted from: Stowe RL, et al. Cochrane Database of Systematic Reviews 2008; Issue 2.

10. Proof of principle for CDS in advanced disease: Clinical evidence from small scale studies StudyDesignResults Mouradian et al, 1990 (N=12) Patients with severe motor complications 24-hour intravenous levodopa infusion for 7-12 days Self rated ‘on’ and ‘off’ states and acute levodopa challenges Motor fluctuations significantly improved with continuous treatment (P<0.02) Following continuous treatment, motor fluctuations decreased by 42% compared with pre-infusion observations Therapeutic window widened by ~50% Stocchi et al, 2005 (N=6) Patients with severe motor complications Continuous daytime infusions of levodopa for 6 months Physician-rated motor assessments Continuous treatment significantly improved duration of ‘off’ periods and time in ‘on’ without dyskinesias as well as severity of dyskinesias (P<0.001) Katzenschlager et al, 2005 (N=12) Patients with ‘on-off’ fluctuations and disabling dyskinesias Daytime SC apomorphine infusion for 6 months Acute apomorphine and levodopa challenges at baseline and 6 months Daily ‘off’ time reduced by 38% with continuous apomorphine Significant reduction in dyskinesias following continuous apomorphine and acute dopaminergic challenges, as rated by dyskinesia rating scales (P<0.01) Mouradian MM, et al. Ann Neurol 1990;27(1):18-23. Stocchi et al. Arch Neurol 2005;62(6):905-910. Katzenschlager R, et al. Mov Disorders 2005;20(2):151-7.

11. Long-term CDS: Clinical evidence AuthorDrugDurationOutcome Nilsson et al, 2001 Duodenal levodopa 4-7 years daytime Decreased dyskinesias and ‘off’ time Manson et al, 2002 Apomorphine SC 4.5 months daytime 43% decrease in dyskinesia; increase in ‘on’ time Stocchi et al, 2002 Lisuride SC4 years daytime 41% reduction in dyskinesia severity Katzenschlager et al, 2005 Apomorphine SC 6 months daytime 39-44% reduction in dyskinesia severity after levodopa and apomorphine challenges Garcia-Ruiz et al, 2008 Continuous apomorphine SC >3 months – 5 years Significant decrease in severity of dyskinesias and ‘off’ time Devos et al, 2009 Duodenal levodopa 1 to 4 years 90% daytime 95% decrease in dyskinesias Katzenschlager R, et al. Mov Disorders 2005;20:151-7. Nilsson D, et al Acta Neurol Scand 2001;104:343-8. Nyholm D, et al. Clin Neuropharmacol 2008;31:63-73. Manson AJ, et al. Mov Disord 2002;17:1235-41. Stocchi F, et al. Brain 2002;125:2058-66. Garcia-Ruiz PJ, et al. Mov Disord 2008;23:1130-6. Devos D, et al. Mov Disord 2009;24:993-1000. AIMS score

12. Current treatment approaches for CDS Levodopa infusions IV* Intraduodenal (carbidopa/levodopa) Levodopa methyl ester* Dopamine agonist infusions (apomorphine, lisuride*) Controlled release oral levodopa Long-acting dopamine agonist (cabergoline) Dopamine agonist skin patch (rotigotine, lisuride) COMT and MAO inhibitors * Experimental formulation W Poewe. Managing Advanced Parkinson’s Disease: Chapter 2 Continuous dopaminergic stimulation in the clinical setting. Aquilonius and Lees (Ed). 2007.

13. Benefits and limitations of CDS Benefits Smooth motor response Potential for ameliorating future fluctuations Compliance Limitations Method of delivery Surgery Logistics of handling infusion systems, pumps ? Tolerance ?? Potential neuropsychiatric problems

14. No tolerance with long-term dopaminergic infusions AuthorDrugDurationTolerance? Colzi et al, 1998Apomorphine subcutaneous 9 months to 9 yearsNo Nyholm et al, 2008Levodopa intraduodenalUp to 10.7 yearsNo Kanovsky et al, 2002Apomorphine subcutaneous 2 yearsNo Manson et al, 2002Apomorphine subcutaneous 34 monthsNo Katzenschlager et al, 2005 Apomorphine subcutaneous 6 monthsNo change in peak anti- Parkinson’s disease response to levodopa and apomorphine challenges Stocchi et al, 2005Levodopa methyl ester intraduodenal 6 monthsNo Garcia-Ruiz et al, 2008 Apomorphine subcutaneous >3 months to 5 years No Devos et al, 2009Levodopa intraduodenal12 to 48 monthsNo Katzenschlager R, et al. Mov Disorders 2005;20(2):151-7;.Nyholm D, et al. Clin Neuropharmacol 2008;31(2)63-73. Manson AJ, et al. Mov Disord 2002;17(6):1235-41. Colzi A, et al. J Neurol Neurosurg Psychiatry 1998;64:573-6. Kanovsky P, et al. Mov Disord 2002;17(1):188-191. Stocchi et al. Arch Neurol 2005;62(6):905-910. Garcia-Ruiz PJ, et al. Mov Disord 2008;23:1130-6. Devos D, et al. Mov Disord 2009;24:993-1000.

15. Summary Plastic changes are at least partly reversible by switching from intermittent therapy to CDS These findings provide the rationale for CDS both at the outset of Parkinson’s disease therapy and later in the course of managing complicated fluctuations Significant advances have been made in developing the practical delivery of CDS Growing evidence supports the benefits of long-term CDS