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Considering the pre-clinical and clinical evidence for continuous dopaminergic stimulation (CDS)

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

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.

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.

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.

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, p185203. ©1990 Reproduced with permission of Taylor & Francis, Inc.

Rationale for CDS in early and advanced Parkinson’s disease
Early
• CDS at the outset of antiParkinson’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

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.

Proof of principle for CDS in advanced disease:
Clinical evidence from small scale studies
Study Design Results
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%
• Continuous treatment significantly improved duration of ‘off’ periods and time in ‘on’ without dyskinesias as well as severity of dyskinesias (P<0.001)
Stocchi et al,
2005 (N=6)
• Patients with severe motor complications
• Continuous daytime infusions of levodopa for 6 months
• Physician-rated motor assessments
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.

Long-term CDS:
Clinical evidence
Author
Nilsson et al,
2001
Manson et al,
2002
Stocchi et al,
2002 et al, 2008
Devos et al,
2009
Drug
Duodenal levodopa
Apomorphine
SC
Lisuride SC
Katzenschlager et al, 2005
Apomorphine
SC apomorphine
SC
Duodenal levodopa
Duration
4-7 years daytime
4.5 months daytime
4 years daytime
6 months daytime
>3 months
5 years
–
1 to 4 years
90% daytime
Outcome
Decreased dyskinesias and ‘off’ time
43% decrease in dyskinesia; increase in ‘on’ time
41% reduction in dyskinesia severity
39-44% reduction in dyskinesia severity after levodopa and apomorphine challenges
Significant decrease in severity of dyskinesias and ‘off’ time
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.

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.

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

No tolerance with long-term dopaminergic infusions
Author Drug Duration Tolerance?
Colzi et al, 1998
Nyholm et al, 2008
Apomorphine subcutaneous
9 months to 9 years
Levodopa intraduodenal Up to 10.7 years
No
No
2 years No Kanovsky et al, 2002 Apomorphine subcutaneous
Manson et al, 2002
Katzenschlager et al,
2005
Apomorphine subcutaneous
Apomorphine subcutaneous
34 months
6 months
No
Stocchi et al, 2005
No change in peak anti-
Parkinson’s disease response to levodopa and apomorphine challenges
No
Garcia-Ruiz et al,
2008
Devos et al, 2009
Levodopa methyl ester intraduodenal
Apomorphine subcutaneous
6 months
>3 months to 5 years
Levodopa intraduodenal 12 to 48 months
No
No
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.

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