Effects of a Dopamine Agonist.pptx

7/28/2019 Effects of a Dopamine Agonist.pptx

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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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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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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.

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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.

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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.

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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

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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

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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

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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...

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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

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Effects of a Dopamine Agonist.pptx