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Considering the pre-clinical and clinical
evidence for continuous dopaminergic
stimulation (CDS)
This educational material has been supported by Abbott
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
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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, p185-203. ©1990 Reproduced with permission of Taylor & Francis, Inc.
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
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%
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.
Long-term CDS:
AIMS score
Clinical evidence
Author
Drug
Duration
Outcome
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 SC
4 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.
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
Limitations
• Smooth motor response
• Potential for ameliorating
future fluctuations
• Compliance
• 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
Apomorphine
subcutaneous
9 months to 9 years
No
Nyholm et al, 2008
Levodopa intraduodenal
Up to 10.7 years
No
Kanovsky et al, 2002
Apomorphine
subcutaneous
2 years
No
Manson et al, 2002
Apomorphine
subcutaneous
34 months
No
Katzenschlager et al,
2005
Apomorphine
subcutaneous
6 months
No change in peak antiParkinson’s disease
response to levodopa and
apomorphine challenges
Stocchi et al, 2005
Levodopa methyl ester
intraduodenal
6 months
No
Garcia-Ruiz et al,
2008
Apomorphine
subcutaneous
>3 months to 5
years
No
Devos et al, 2009
Levodopa intraduodenal
12 to 48 months
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