Levodopadyskinesia Incidence by Age of Parkinson's Disease Onset

1
(No Transcript)
2
Levodopa-dyskinesia Incidence by Age of
Parkinson's Disease Onset

• PD onset N 5-year dyskesnia incidence
  with dyskinesia
• 40-49 5 2 40
• 50-59 19 10 53
• 60-69 35 9 26
• 70-79 25 4 16
• 80-89 7 1 14
• (Kumar N, 2004 Rome)

3
Experience of Pergolide in the Treatment of
Chinese Parkinsonian Patients with Dose-related
Fluctuations

• An open-label trial, 20 weeks, 20 patients with
  motor fluctuations, 19 patients completed
• The mean dosage of pergolide was 2.89 mg per day
  (range 2.25 - 3.50)
• The mean dosage of levodopa before entry into the
  study was 605.3 mg/day.
• The mean dosage of levodopa after completion of
  the study was 563.2 mg/day (pgt0.05).
• (Shan DE, Chin Med J 199556312)

4
Experience of Pergolide in the Treatment of
Chinese Parkinsonian Patients with Dose-related
Fluctuations

• The total motor score improved by 34.1 during
  the "on" period and by 34.8 during the "off"
  period (p lt 0.001).
• The recorded daily off time decreased from 40.3
  to 11.5 (p lt 0.001).
• Hallucination (40), worsening of peak-dose
  dyskinesia (35), and lowering of blood pressure
  (lying 140/79 to 120/72, standing 122/75 to
  111/69) were major adverse effects.
• (Shan DE, Chin Med J 199556312)

5
Pergolide Associated Valvulopathy A Belgian
Experience

• 5 pergolide associated valvulopathies.
• All treated with pergolide (between 5.5 and 15 mg
  daily), presented heart failure.
• 9 had ultrasound plurivalvulopathies, mainly the
  tricuspid, with restricted leaflet motion and/or
  pulmonary hypertension
• The occurrence remains actually rare but the real
  incidence has yet to be defined.
• (Evrard F.L. 2004 Rome)

6
Treatment of Parkinsons Disease with Pergolide
and Relation toRestrictive Valvular Heart Disease

• To define pergolide-induced disease, presence of
  a regurgitant jet by color doppler is inaccurate.
  A very comprehensive method is to measure tenting
  distance and area.
• Restrictive valvular heart disease was present in
  26 (33) patients in the pergolide group.
• Significant correlation was noted between
  cumulative doses of pergolide and tenting areas
  of the mitral valves.
• Mean systolic pulmonary artery pressures were
  39.3 mm Hg in the high-dose group versus 38.5 mm
  Hg in the low-dose group and 31 mm Hg in
  controls.
• (Van Camp G, Lancet 20043631179)

7
Severe Multivalvular Heart Disease A New
Complication of the Ergot Derivative Dopamine
Agonists

• 4 new cases treated with pergolide and
  cabergoline.
• The pathogenesis is suspected to involve
  serotonin-mediated abnormal fibrogenesis by means
  of the 5-HT2B receptors, which are expressed in
  the fibroblasts of heart valves.
• (Horvath, Mov Disord 200419656)

8
Pergolide in Parkinsons Disease Time for a
Change?

• Guy Van Camp report that higher than expected
  rates of restrictive valvular heart disease occur
  in patients with Parkinsons disease treated with
  pergolide. Given that 27 of 78 patients were
  affected, we are surprised that pergolide was
  stopped in only six of 78 cases.
• We produced an equivalence conversion chart for
  available dose levels between five dopamine
  agonists, which guides the clinician in switch.
• (Grosset KA, Lancet 20043631907)

9
The Diagnosis and Management of Pergolide-induced
Fibrosis

• Eleven papers reported 22 patients who developed
  symptomatic fibrosis.
• The dosage of pergolide ranged from 1-8 mg/day,
  and duration of exposure from 1-8 years.
• Pergolide can induce fibrosis after relatively
  brief exposure at low dose.
• The maximum time to diagnosis was 36 months.
• (Agarwal P. 2004 Rome)

10
The Diagnosis and Management of Pergolide-induced
Fibrosis

• The most common presenting symptom was dyspnea
  (13/23 patients).
• Unilateral or bilateral leg edema, cough, chest
  pain, and dysuria were also seen.
• In six patients the ESR rate was elevated, from
  40-127 mm/hour.
• Patients should undergo echocardiography and CT
  scan of the chest, abdomen and pelvis to rule out
  fibrosis.
• (Agarwal P. 2004 Rome)

11
The Diagnosis and Management of Pergolide-induced
Fibrosis

• Most patients required an invasive procedure to
  secure the diagnosis.
• Four patients were treated with steroids with
  dramatic benefit .
• Pericardectomy and ureteral stenting were
  necessary in some cases.
• Three patients did not improve despite
  discontinuation of the drug.
• (Agarwal P. 2004 Rome)

12
(No Transcript)
13
Three Cases of Peripheral Edema Caused by
Prolonged Use of Ropinirole

• The clinical spectrum varied from asymmetrical
  lower extremity edema to generalized severe edema
  with erythema.
• Edema occurred months after therapy initiation,
  was dose dependent (24, 24, 8 mg), misdiagnosed
  in all 3 cases and resistant to medical therapy.
• Discontinuation of ropinirole produced complete
  resolution of edema.
• Initiation of another dopaminergic agonist should
  be done cautiously.
• (Apetauerova D, 2004 Rome)

14
(No Transcript)
15
Dopamine Receptor Agonists in Current Clinical
Use Comparative Dopamine Receptor Binding
Profiles Defined in the Human Striatum

• D1 (nM) D2 (nM) D2 (nM) D3 (nM)
• 3HSCH23390 3HRaclopride
  3HSpiperone 3HPD128907
• Dopamine 2729 117000 145.6
  69.00
• Bromocriptine 119.6 2.9
  4.87 30.45
• Cabergoline 1462 0.61
  1.63 1.27
• Lisuride 6.7 0.95
  1.24 1.08
• Pergolide 447 10.3
  36.6 0.86
• Pramipexole gt100000 79500 473.4
  0.97
• Ropinirole gt100000 98700 3277
  34.89
• (Gerlach M, J Neural Transm 20031101119)

16
Experience of Ropinirole in the Treatment of
Chinese Parkinsonian Patients with Dose-related
Fluctuations

• Randomized, double-blind, bromocriptine-controlled
  , four months,
• 22 patients with motor fluctuations in each group
• 19 patients completed in the ropinirole group, 21
  patients completed in the bromocriptine group
• The mean dosage of ropinirole 9 mg, the mean
  dosage of bromocriptine 17.5 mg
• (Shan DE)

17
Experience of Ropinirole in the Treatment of
Chinese Parkinsonian Patients with Dose-related
Fluctuations

• Ropinirole Bromocriptine
• Off time 50.0 44.5
• Off time -16 -12
• (pgt0.05)
• UPDRS(motor) 32.8 30.9
• -30 UPDRS 10 7
• (pgt0.05)
• (Shan DE)

18
(No Transcript)
19
Efficacy, Safety, and Tolerability of Pramipexole
in Untreated and Levodopa-treated Patients with
Parkinson's Disease

• Randomized, double-blind, placebo-controlled, 15
  weeks, 150 patients, 77 in the placebo group, 73
  in the pramipexole group, 70 were on levodopa
• The mean number of off hours/day for patients
  receiving pramipexole improved (mean baseline
  value, 7.07 hours mean end-of-treatment value,
  6.15 hours), while that for patients receiving
  placebo worsened (5.59 hours vs. 6.87 hours).
• (Wang KS, J Neurol Sci 200321681)

20
Efficacy, Safety, and Tolerability of Pramipexole
in Untreated and Levodopa-treated Patients with
Parkinson's Disease

• The mean improvement for the pramipexole/no
  levodopa group relative to the placebo/no
  levodopa group at week 15 was 10.93 points (i.e.,
  -14.43 points minus -3.50 points).
• The mean improvement for the pramipexole/levodopa
  group relative to the placebo/levodopa group at
  week 15 was 9.04 points (i.e., -10.26 points
  minus -1.22 points).
• (Wang KS, J Neurol Sci 200321681)

21
(No Transcript)
22
(No Transcript)
23
(No Transcript)
24
(No Transcript)
25
Alterations in Striatal Neuropeptide mRNA
Produced by Repeated Administration of L-DOPA,
Ropinirole or Bromocriptine Correlate with
Dyskinesia Induction in MPTP-treated Common
Marmosets

• Using in situ hybridisation histochemistry to
  compare striatal preproenkephalin-A (PPE-A)
  receptor mRNA expression as markers of the
  indirect pathway, and striatal preprotachykinin
  (PPT) mRNA and preproenkephalin-B (PPE-B,
  prodynorphin) mRNA expression as markers of the
  direct pathway.
• MPTP-induced destruction of the nigro-striatal
  pathway markedly increased the level of PPE-A
  mRNA in the caudate nucleus and putamen and
  decreased the levels of PPT and PPE-B mRNA
  relative to normal animals.
• (Tel BC, Neurosci 20021151047)

26
Alterations in Striatal Neuropeptide mRNA
Produced by Repeated Administration of L-DOPA,
Ropinirole or Bromocriptine Correlate with
Dyskinesia Induction in MPTP-treated Common
Marmosets

• Repeated treatment with L-DOPA for 30 days
  produced marked dyskinesia but had no effect on
  the MPTP-induced increase in PPE-A mRNA in the
  caudate nucleus and putamen. In contrast, L-DOPA
  treatment normalised the MPTP-induced decrease in
  the level of PPT and PPE-B mRNA.
• Repeated treatment with ropinirole produced
  little or no dyskinesia but markedly reversed the
  MPTP-induced elevation in PPE-A mRNA in the
  caudate nucleus and putamen. However, it had no
  effect on the decrease in PPT or PPE-B mRNA.
• (Tel BC, Neurosci 20021151047)

27
Predicting Incident Non-motor Complications of
Dopaminergic Therapy in Patients with Early
Parkinson's Disease A Secondary Analysis of the
CALM-PD Trial

• Pramipexole Levodopa
• Edema 42.4 14.0
• Somnolence 36.4 21.3
• Urine incontinence 3.3 10.7
• Cellucilitis 4.6 0
• (Biglan KM, 2004 Rome)

28
Predicting Incident Non-motor Complications of
Dopaminergic Therapy in Patients with Early
Parkinson's Disease A Secondary Analysis of the
CALM-PD Trial

• Somnolence
• 66 mild, 27 moderate, 7 severe
• 12 patients drop out, 8 of them had sudden onset
  of sleep attack
• 1 patient had motor vehicle accident
• Edema
• 64 mild, 31 moderate, 5 severe
• (Biglan KM, 2004 Rome)

29
(No Transcript)
30
Dopamine Agonist Monotherapy in Parkinson's
Disease

• 123I-beta-CIT SPECT
• Those patients given pramipexole had
  significantly reduced loss of striatal uptake at
  46 months compared with those given levodopa
  (16.0 vs 25.5).
• 18F-DOPA PET
• Patients given ropinirole had significantly
  reduced loss of striatal uptake at 24 months
  compared with those given levodopa (13 vs 20).
• (Clarke CE, Lancet 20023601767)

31
Dopamine Agonist Monotherapy in Parkinson's
Disease

• This work has been criticized as the SPECT
  results may have resulted from a differential
  effect of the agonist and levodopa on the
  regulation of the dopamine transporter, thereby
  influencing the imaging outcome measure.
• Other criticisms include insufficient data on the
  use of the potential neuroprotectant selegiline.
• (Clarke CE, Lancet 20023601767)

32
REAL and CALM What Have We Learned?

• The 123I -CIT SPECT measurement used by CALM-PD
  lacks sensitivity to clinical change, one can
  estimate that striatal ratio might change by a
  maximum of 8-10 with each 10-point change in
  total UPDRS.
• In the CALM-PD study, both subgroups changed
  clinically by an average of 4 total UPDRS points.
  it can be estimated that striatal ratio might
  have been expected to change by a maximum of
  4-5.
• (Morrish PK, Mov Disord 200318839)

33
REAL and CALM What Have We Learned?

• In CALM-PD, the striatal ratio changes by 16 of
  baseline in one arm and 25.5 in the other. It
  can be seen that such enormous changes in SPECT
  measurement with such a small change measured
  clinically cannot possibly be the result of
  disease progression.
• The difference in the two arms of the trial might
  be a consequence of different effects of the
  drugs on the dopamine receptor
• (Morrish PK, Mov Disord 200318839)

34
REAL and CALM What Have We Learned?

• REAL-PET is a more satisfactory study. It is much
  larger, the patients have progressed at a
  clinical rate that is more typical, the technique
  used has greater sensitivity to clinical change,
  the methodology has ensured blinding analysis,
  and patients were scanned on medication at both
  the start and finish of the study.
• (Morrish PK, Mov Disord 200318839)

35
REAL and CALM What Have We Learned?

• When the entire cohort was assessed, the
  difference between the subgroups did not reach
  statistical significance.
• A decision was made to exclude from the analysis
  11 of patients in the trial on the grounds that
  the result of their initial PET scan was within
  the normal range.
• This decision is questionable.
• (Morrish PK, Mov Disord 200318839)

36
The Effectiveness of Pergolide and Cabergoline as
an Adjunct to Levodopa in Parkinson's Disease
(Double-blind, 12 months)

• Pergolide Cabergoline
• Patients 20 20
• ? UPDRS plt0.001 plt0.001
• ? LD dose 225mg 175mg
• ? Off-period 2.1h 1.2h
• ? Dyskinesia 59 51
• SE nausea, hallucination
• (Subutay NO, 2004 Rome)

37
Ropinirole versus Pergolide as Adjunctive Therapy
to Levodopa in Parkinson's Disease(open-trial? 1
month 2 months ?)

• Ropinirole Pergolide
• Patients 29 29
• Dose 6.24mg 2.21mg
• ? UPDRS 22.4 9.5
• ? LD dose 55.2 34.5
• ? Off-period 58.6 37.9
• SE 17.2 31
• (Unal E, 2004 Rome)

38
Ergot Side-effect Issues in Dopamine Agonist
Treatment of Parkinson's Disease

• Out of 99 patients, 88 (89) switched to a
  non-ergot agonist.
• Drug switching was conducted overnight based on a
  dose equivalence table, adjusted on a
  case-by-case basis to "higher" or "lower" than
  equivalent.
• The baseline treatment was pergolide (78),
  cabergoline (17), and bromocriptine (5) 51
  were on dopamine agonist monotherapy.
• Switching was to pramipexole in 84 and
  ropinirole in 16.
• (Grosset KA, 2004 Rome)

39
Ergot Side-effect Issues in Dopamine Agonist
Treatment of Parkinson's Disease

• Dose was "equivalent" in 54 (61), "lower" in 20
  (23), and "higher" in 14 (16).
• Adverse events occurred in 26, and were less
  common at "equivalent" (20) than "lower" (30)
  or "higher" (43) doses.
• After 11 months, 82 were on their switch
  agonist.
• Effective overnight switching to non-ergot
  dopamine agonists is achievable with high therapy
  retention rates and an acceptable short-term
  adverse event profile.
• (Grosset KA, 2004 Rome)

40
(No Transcript)
41
Combining Dopamine Agonists of Different Dopamine
Receptor Profiles in Advanced Parkinson's Disease

• Conventional strategies for 38 of 413 patients
  were not successful.
• We administered a combination of cabergoline and
  pramipexole in 24 of 27 patients.
• Cabergoline dosages ranged between 2 and 10 mg,
  pramipexole between 0.72 and 3.15 mg.
• In 22 of 27 cases levodopa was successfully
  reduced by a mean of 35.
• (Sixel-Doering F, 2004 Rome)

42
Combining Dopamine Agonists of Different Dopamine
Receptor Profiles in Advanced Parkinson's Disease

• A significant reduction of dyskinesia and off
  fluctuations in all of the 27 cases.
• Medication-induced hallucinosis had been present
  in 15 cases beforehand, 2 patients newly
  developed hallucinations could be well controlled
  by small doses of quetiapine.
• The combination of two dopamine agonists with
  different plasma half life and receptor binding
  properties to be a successful treatment option
• (Sixel-Doering F, 2004 Rome)

43
Dopamine Agonist Treatment of Parkinson's Disease
in the Elderly

• 339 patients over seventy years of age
• When titrated slowly, adverse effects were mild
  and did not limit treatment for most patients.
• Once or twice daily dosing was better tolerated
  than more frequent administration.
• Improvement of parkinsonism, including postural
  reflexes, and reduced motor fluctuations were
  frequently found.
• Age may be a less important factor in choosing
  therapy than current guidelines suggest.
• (Isaacson SH, 2004 Rome)

44
(No Transcript)
45
(No Transcript)
46
(No Transcript)
47
(No Transcript)
48
Subcutaneous Apomorphine Infusion vs. STN-DBS
Clinical and Neuropsychological Follow-up at 12
Months in Patients with Complicated PD

• 12 patients underwent APO and 20 STN-DBS.
• At 12 months APO treatment (73.5 mg/day) resulted
  in a significant reduction of off (-22) and
  dyskinesias (-23). Levodopa equivalent doses
  were reduced from 630 mg baseline to 528 mg/day.
• At 12 months STN-DBS determined significant
  clinical improvement in terms of reduction of
  daily off time (-28) and dyskinesias (-37) as
  well as levodopa equivalent doses (770 to 310).
• (Antonini A, 2004 Rome)

49
Subcutaneous Apomorphine Infusion vs. STN-DBS
Clinical and Neuropsychological Follow-up at 12
Months in Patients with Complicated PD

• STN-DBS resulted in greater reduction of
  dopaminergic medications.
• STN-DBS can provide a 24-hour motor benefit.
• STN-DBS , unlike APO, appears to be associated
  with a significant worsening of neuropsychiatric
  scales.
• (Antonini A, 2004 Rome)

50
Initial Therapy in Parkinson's Disease Should Be
with a Dopamine Agonist YES

• Dopamine agonists have pharmacological advantages
  over L-Dopa including significantly longer
  half-lives, direct receptor agonism, lack of
  oxidative metabolism and neuroprotective
  properties in experimental models.
• A number of randomised controlled prospective
  long-term trials have compared the outcome of
  early monotherapy with different DA-agonists
  (pramipexole, ropinirole, pergolide, cabergoline)
  versus L-Dopa. Results have been remarkably
  consistent between trials and demonstrate a
  significantly decreased risk of motor
  complications with early monotherapy with
  DA-agonists.
• (Poewe W, 2004 Rome)

51
Initial Therapy in Parkinson's Disease Should Be
with a Dopamine Agonist YES

• Side effect related drop-out rates were not
  different in all those trials, however somnolence
  was generally more common in dopamine agonist
  treated patients as were drug-induced
  hallucinations.
• Two recent studies have found a 30 to 40
  lesser decline of either dopamine transporter
  binding using SPECT or putaminal 18-F-Dopa uptake
  using PET with DA-agonist treatment versus
  L-Dopa.
• (Poewe W, 2004 Rome)

52
Is Levodopa-induced Dyskinesias Risk Decreased in
Parkinsonian Patients Initially Treated with
Dopamine Agonist? A Longitudinal Study Among 425
Patients

• 63 patients initially treated with dopamine
  agonists, 362 patients treated first with
  levodopa
• All but one patients initially treated with
  dopamine agonist finally needed levodopa 3.27
  years later
• LIDs occurred in 42 out of 63 patients initially
  treated with dopamine agonist and in 211 out of
  362 treated first with levodopa
• Time free from LIDs calculated from
  antiparkinsonian treatment onset, showed
  significant difference between Kaplan-Meier
  survival curves in favour of initial dopamine
  agonist treatment until 4 years PD evolution.
• (Ouchchane L, 2004 Rome)

53
Is Levodopa-induced Dyskinesias Risk Decreased in
Parkinsonian Patients Initially Treated with
Dopamine Agonist? A Longitudinal Study Among 425
Patients

• No significant difference was shown for 5 years
  PD evolution or longer time evolution (15 years).
  
• In our study, starting treatment with a dopamine
  agonist did not reduce LIDs risk on long-term
  evolution of PD patients.
• It even suggests that, as soon as levodopa become
  necessary, patients initially treated with
  dopamine agonist have higher risk of LIDs
  (2.62x).
• (Ouchchane L, 2004 Rome)

54
Is Levodopa-induced Dyskinesias Risk Decreased in
Parkinsonian Patients Initially Treated with
Dopamine Agonist? (Comments from Lang A)

• Not a randomized study
• Not potent dopamine agonist used
• Piribedil 63
• Bromocriptine 19
• Lisuride 8
• Ropinirole 8
• Cabergoline 1.5

55
Reduced Dyskinesias with Ropinirole in a
Naturalistic 8.5-year Follow-up of Patients with
Early Parkinson's Disease (PD) Who Had Initially
Received Ropinirole or L-dopa

• Of 130 pts completing study 056, 60 entered the
  present study.
• During 8.5-year follow-up, 42 of the ropinirole
  arm developed dyskinesias, significantly lower
  than the 71 of the L-dopa arm.
• The median time to develop dyskinesias was
  significantly longer in the ropinirole (8.3yrs)
  than the L-dopa arm (7.3yrs).
• This benefit of ropinirole was present whether or
  not supplementary L-dopa was used.
• (Rascol O, 2004 Rome)

56
Potential Advantages of the Dopamine Agonists

• By-pass dopaminergic system
• independent of enzyme conversion and release
• Do not compete for transport at intestinal or BBB
  level
• Parenteral administration is possible
• Longer half-life
• Delay the appearance of levodopa complications
• Diminish oxidative stress - neuroprotective
• Selective receptor activation may be possible

57
Potential Disadvantages of the Dopamine Agonists

• Less effective than levodopa
• More adverse effects
• Higher costs

58
Dopamine Agonist Therapy in Early Parkinson's
Disease A Systematic Review of Randomised
Controlled Trials

• 28 randomised trials of DA therapy involving over
  5000 patients with early PD were identified.
• Odds Ratio
• less likely to develop dyskinesia 0.48
• less likely motor fluctuations 0.74
• less likely dystonia 0.64
• more likely to develop edema 2.90
• more likely somnolence 2.73
• more likely hallucinations 2.21
• more likely nausea 1.89
• more likely constipation 1.81
• more likely dizziness 1.58
• more likely insomnia 1.41
• (Ives NJ, 2004 Rome)