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EFFECTSOFA DOPAMINEAGONISTONTHE PHARMACODYNAMICSOF
LEVODOPAIN PARKINSON DISEASE
Oleh : dr. Euginia Putri Permatasari P
Pembimbing : dr.Muhammad Hamdan spS (K)
1
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Treatment of Parkinson disease commonlyincludes levodopa and dopamine agonists;however,the interaction of these 2 drugs is poorlyunderstood
BACKGROUND
Objective
To examine the effects of a dopamineagoniston the motor response to levodopa. 2
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DesignDouble-blind, randomized,
placebo-controlled,
crossover clinical trial.
SettingAmbulatory academic
referral center.
Patients
Thirteen patients with
idiopathic Parkinson
disease taking levodopa and
experiencing motor
fluctuations
and dyskinesia.3
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4
Interventions
Eligible individuals were randomly assigned
to receive pramipexole dihydrochloride or placebo
for 4 weeks followed by a 2-hour intravenous levodopainfusion on consecutive days at 2 rates and with
blinded assessments. They were then crossed over to the
alternate oral therapy for 4 weeks followed by levodopa
infusion and reassessment.
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5
Main OutcomeMeasures
Change in finger-tapping
speed, measured using the area under the curve (AUC)
for finger taps per minute across time; peak
fingertapping
speed; duration of response; time to ON (defined
as a 10% increase in finger-tapping speed above
baseline);
walking speed; and dyskinesia AUC.
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Results
Pramipexole with levodopa infusion increased
finger-tapping speed beyond the change in baseline
by a mean (SE) of 170 (47.2) per minuteminutes
(P=.006) and more than doubled the AUC for fingertapping
speed. Pramipexole increased peak fingertapping
speed by a mean (SE) of 18 (8.5) taps per minute(P=.02) and improved mean (SE) walking speed (15.9
[0.70] vs 18.9 [0.70] seconds, P=.004). Pramipexole prolonged
duration of response after levodopa infusion and
shortened time to ON. Pramipexole increased mean (SE)
baseline dyskinesia scores (26.0 [5.85] vs 12.1 [5.85]points, P=.05) and peak dyskinesia scores with levodopa
infusion.
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Conclusions
Pramipexole augmented the motor response
to levodopa beyond a simple additive effect and
increased the severity of levodopa-induced dyskinesia.When considering a combination of these therapies, an
appropriate balance should bemaintained regarding gain
of motor function vs worsening of dyskinesia.
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INTRODUCTION
PHARMACOLOGIC TREATMENT of Parkinson
disease (PD) commonly includes levodopa
and dopamine agonists (DAs).
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The mechanism of
DAs enhance the
response to
levodopa treatment
is uncertain
DA as initial
treatment of PD
delays the onset of
motor complications.
Levodopa is added
when DAs are no
sufficiently effective. The combination of aDA with oral levodopa
generally increases
ON time.
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DAs have a low propensity toproduce dyskinesia as monotherapy How do they affectlevodopa-induced dyskinesia?
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We performed a double-blind, randomized, placebo
controlled, crossover clinical trial to examine the
interaction of DAs and levodopa by measuring the
motor response to a 2-hour intravenous levodopa
infusion in patients with PD taking a DA, pramipexoledihydrochloride, for 1 month and taking placebo for 1
month.
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Patients aged 30 to 80
years with idiopathic PD.
Approved the informedconsent.
atypical features of
parkinsonism
Mini-Mental State
Examination
score less than 25 Had unstable
cardiovascular disease
Active peptic ulcer disease
InclutionExclution
METHODS
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Patients were screened using finger tapping
In the practically defined OFF motor state, having been without levodopaovernight, defined ONmotor state, approximately 1 hour after taking their
usual levodopa dose.
To qualify, they had to have a minimum of 10% improvement infinger-tapping speed in the ON state.
METHODS...
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13 patients of
PD
DA 1,0mg/8hrs
Placebo
Levodopa iv0,5mg/kg/hrs
1,0 mg/kg/hrs
Effect?
2 hours
Effect?
4weeks
PlaceboLevodopa iv
0,5mg/kg/hrs
1,0 mg/kg/hrs
Levodopa iv0,5mg/kg/hrs
1,0 mg/kg/hrs
Levodopa iv0,5mg/kg/hrs1,0 mg/kg/hrs
DA 1,0mg/8hrs
4weeks 2 hours
Effect?
Effect?
random
random
A
B
AB
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Change in finger-tapping speedPRIMARY
The AUC for dyskinesia,
peak fingertapping speed
duration of response
time to ON
walking speed
Unified Parkinsons DiseaseRating Scale(mUPDRS)
Mood, anxiety, and fatigue.
SECONDARY
OUTCOMEMETHODS...
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METHODS..
They practiced finger-tapping scoring 3 times on theevening of admission
Their last levodopa dose was given no later than at10PM, and all other PD medications were withheld after 10PM.
At 7 AM the next morning, a dose of the study drug wasgiven, and an intravenous line was placed.
An intravenous levodopa infusionwas administeredcontinuously for 2 hours starting at 9 AM at a constantrate of 0.5 mg/kg/h (threshold rate) or 1.0 mg/kg/h(therapeutic rate). The infusion rate was blinded andrandomized.
The infusion was stopped at 11 AM.
After 2 PM and when patients were deemed to be OFF,the usual antiparkinson medications were reinstituted 16
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METHODS..
Finger-tapping speed, walking speed (timed and
number of steps), and dyskinesia were measured
by blinded research nurses, and patients completed
visual analog scales for anxiety, fatigue, andmood
every 30 minutes from 7 AM until 2 PM.
Baseline finger-tapping scores were calculated as
the mean of the 7:30, 8, 8:30, and 9 AM scores
when patients went overnightwithout
antiparkinsonmedications, except for placebo orpramipexole at 7 AM, but before levodopa infusions
started at 9 AM.
17
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METHODS..
Dyskinesia was graded on a scale from 0 to 4 points:
0 : none
1 : mild
2 : definite/mild to moderate
3 : moderate may interfere with some activities;4 : severe, markedly impairs voluntary activities in
the face, neck, and trunk and each of the 4 limbs
Total score (range: 0-28) was assigned.
Ambulation was assessed by measuring the time it took
the patient to stand up from a chair, walk 6 m, turnaround, return to the chair, and sit.
An mUPDRS was collected at 9 AM, just before thelevodopa infusion was started, and at 11 AM, at peaklevodopa concentration. 18
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STATISTICAL ANALYSIS
To compare the pramipexole effect and the infusion
effect, the interaction between pramipexole and
infusion, and the carryover effect due to the study
design, we used the mixed model.
The Bayesian information criterion was used to
determine a covariance structure for the model.
All analyses were performed using SAS version 9.1
(SAS Institute Inc, Cary, North Carolina), and P.05
was considered statisticallysignificant.
19
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STATISTICAL ANALYSIS ...
Change in the total finger-tapping score was
calculated as the total finger-tapping score from
9:30 AM to 2 PM minus the baseline finger-tapping
score from 7:30 to 9 AM.
The AUC was calculated from the scores from 9:30
AM until 2 PM minus the mean baseline scores
from 7:30 to 9 AM, setting any negative scores to
zero.
20
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STATISTICAL ANALYSIS ...
The peak score was the single fastest finger
tapping time or dyskinesia score.
Onset of clinical response was measured as the
time to a 10% increase in the finger-tapping score,
and time to ON was defined as the time point after
the start of the infusion at which a 10%
improvement in the fingertapping score above the
mean baseline score was attained in patients who
had an ON response. Duration of ON timewas determined as the total
time that finger tapping was at least 10% faster
than the mean baseline value. 21
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RESULT
22
Abbreviations: DA, dopamine agonist; LD, levodopa; mUPDRS, motor score of the Unified Parkinsons Disease Rating
Scale; PD, Parkinson disease.a Calculated as immediate-release LD (1.25 with a Component Object Model Transaction Integrator) 75% of continuous-
release LD.bDropped out before the first infusion.cDropped out before the second infusion
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RESULT...
23Figure 1. Finger taps per minute vs time in 13 patients with
idiopathic Parkinson disease. LD indicates levodopa.
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RESULT..
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Abbreviations: AUC, area under the curve; LD, levodopa.
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RESULT...
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Figure 2. Dyskinesia vs time in 13 patients with idiopathic Parkinson disease.
LD indicates levodopa.
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COMMENT
26
What are the clinical implications of these studies?
The clinical implications of these studies are :
DAs markedly augment the antiparkinsonian and
dyskinetic actions of levodopa.
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Addition of a DA to levodopa would augment the
antiparkinsonian
benefits of levodopa by :
1. DA improved Finger Tapping score
2. Increasing Peak of Finger Tapping Speed
3. Prolonged duration respon of Levodopa
4. Sooner respon time ON of Levodopa.
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CONCLUSION
28
When considering a combination of these dopaminergic therapies,an appropriate balance should be maintained regarding gain of motor
function vs worsening of dyskinesia.
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TELAAH KRITISI
29
Apakah alokasi subyek
penelitian ke kelompok terapi
atau kontrol betul-betulsecara acak ( random ) atau
tidak ?
YA. Pada jurnal ini alokasi subyek penelitian dilakukan secara
acak ( random ),double-blind dan selanjutnya dilakukan
placebo-controlled,crossover dimana dapat mengeliminasi
perbedaan pasien secara individual terhadap efek terapi
secara keseluruhan. Tampak pada hal.28 para 5, para.7 dan
para.13.
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TELAAH KRITISI...
30
Apakah semua keluaran
dilaporkan ?
YA, didalam jurnal penelitian ini telah dilaporkan keseluruhan
outcome dari penelitian pada 13 subyek yang diamati dan
dicatat frekuensi taping jari per menitnya dan diskinesia tampakpada hal. 29 figur I,Tabel II, dan Figur 2.
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TELAAH KRITISI...
31
Apakah lokasi studimenyerupai lokasi anda
bekerja atau tidak ?
YA, Penelitian ini dilakukan di RS.Pendidikan pusatrujukan di OHSU Portland.
Tampak pada hal 27 Setting : Ambulatory academic
referral centre
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TELAAH KRITISI...
32
Apakah kemaknaan statistik
dan klinis dipertimbangkan
/dilaporkan ?
YA, Kemaknaan statistik dan klinis dilaporkan di dalam
hasil penelitian. Dalam penelitian ini dilaporkan efek
pemberian Pramipexole pada pasien bradikinesia dan efek
pemberian Pramipexole terhadap respon motorik dengan
kombinasi pemberia Levodopa,seperti yang dijelaskanpada hal.29-30 tabel 2,figur I dan figur 2
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TELAAH KRITISI...
33
Apakah tindakan terapi
yang dilakukan dapat
dilakukan ditempat anda
bekerja atau tidak
YA dapat, Berdasarkan hasil dari penelitian ini dapat
disimpulkan bahwa pemberian Pramipexole yang
dikombinasikan dengan Levodopa dapatmemperbaiki fungsi motorik dan dapat menurunkan
tingkat keparahan diskinesia akibat Levodopa.
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TELAAH KRITISI...
34
Apakah subyek penelitian
diperhitungkan dalam
kesimpulan ?
YA, Didalam penelitian ini, pada awalnya di dapatkan 13
subyek yang memenuhi kriteria inklusi, tetapi dari 13 subyektersebut terdapat 3 subyek yang di Drop Out, sehingga hanya
10 subyek yang dapat melanjutkan penelitian ini. Tampak pada
Result hal. 29
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DANKE
35