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Summary Sifrol Farmakologi
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Pramipexole (Sifrol Mirapex)Parkinsons DiseaseBoehringer Ingelheim GmbH
Issues: Medical Management of PDEarly Disease
* Establish symptomatic control* Avoid motor complications* Modify progression
Advanced Disease
*Maintain symptomatic control*Control motor-complications*Control non-motor complications
Dyskinesias and motor fluctuations in a community-based study of PD (Schrag et al, 2000)
R E S U L T S*Dyskinesias in 28 % of the patients
*Motor fluctuations in 40 % of the patients
*Predictors for the evolution of motor fluctuations:- Disease duration- LD dose
*Predictors for the evolution of dyskinesias:- Duration of treatment
Levodopa-induced Dyskinesias in Early Onset PDDuration of LD % of pts. with dyskinesiasQuinn et al, 1987. (N=40) Schrag et al, 1998. (N = 99)6 mths 41 % .2 years 63 % .5 years 94 % 91 %6 years 100 % .> 10 years .100 %
Shortcomings of L-DOPAPharmacological- pro-drug- absorption and transport failure- short half-life- oxidative metabolism (?)
Clinical- short duration of action- motor complications- no effect on progression
Advantages of Dopamine agonists in the treatment of PD*Direct DA-receptor-stimulation*D1-/D2-subspecificity *No transport competition (GI-tract, BBB)*Longer half-life than levodopa (Ropinirole, Pramipexole, Pergolide, Cabergoline)*No oxidative metabolism*Neuroprotection in vitro- radical scavenging- antioxidative action- antiapoptotic action
CALM-PD: Pramipexole vs LevodopaDyskinesiaWearing OffOn-off Effects*P = .01.P = .001.P = .11.Incidence of Major Motor Complications at 2 Years*
Levodopa Induces a Higher Incidence of Dyskinesia Than Dopamine Agonist TherapyCALM-PD2 yrCabaser 095 yrRequip 0565 yr50
40
30
20
10
0Patients with dyskinesia Adapted from Hubble J. Neurology. 2002;58(suppl 1):S42-S50.LevodopaPramipexoleCabergolineRopinirole
Dopamine Agonists vs Levodopa:Adverse Effect (%)50204.828.432.2612323.37.336.7104.3179.3Hallucinations326.52232.4Somnolence 4037.4 3936.4NauseaPelmopet4Peg LDCabaser 093CAB LDRequip 0562ROP LDCALM-PD1PRX LDAEsROP = ropinirole; CAB = cabergoline; PRX = pramipexole; Peg = pergolide; LD = levodopa.
Parkinson Study Group. JAMA. 2000;284:1931-1938.Rascol O, et al. N Engl J Med. 2000;342:1484-1491.Rinne UK, et al. Neurology. 1997;48:363-368.Oertel WH. Mov Disord. 2000;15(suppl 3):4, Abstract M86.
Dopamine Agonists as initial monotherapy in PD - Results from long-term RCTs - -Significantly less motor complications compared to L-Dopa
-About one third remain on agonist monotherapy over 3 - 5 years -Symptomatic efficacy less than with L-Dopa (? clinical relevance)
-Increased incidence of hallucinosis compared to levodopa
Evidence-based review of PD therapiesEfficacy of DA-Agonists*Prevention of disease progression--> insufficient evidence
*Symptomatic control--> efficacious: DHEC, Bromocriptine, Cabergoline, Pergolide, Ropinirole, Pramipexole--> likely efficacious: Apomorphine, Lisuride--> insufficient evidence: PiribedilMDS-Review, Movement Disorders 2002; 17, Suppl. 4
Preclinical rationale and evidence for the use of DA in PDT. Shapira
Potential disease modifying effects of DADA are capable of reducing cell death in a variety of model systems in response to a range of toxinsMTPTrotenonehydroxydopaminelevodopadopamine
Protective properties of pramipexoleIn neuronal cell cultures against a range of toxinsNeuroprotective action in primate and rodent models of MPTP toxicity
Mechanism of action of PPX mediated neuroprotection not yet fully understoodPPX is capable of blocking the pathway to apoptosisPPX may directly act upon mitochondrial permeabilityEffects of PPX may be independent of the DA receptor
Imaging data from long-term studies with dopamine agonistsKenneth L. Marek, MD
Outcome Measures for PD: NeuroprotectionPrimary CNS Process
Compensatory CNS Processes
Functional/Motor ConsequencesImaging
Motor RatingsClinical Milestones Assessment
Neuroimaging Assessment of PD Progression DAT--CIT, CFT, IPT6%-11% reduction/yearStaffen et al, J Neural Transm, 2000Nurmi et al, Mov Disord, 2000 Marek et al, Neurology, 2001Pirker et al, Mov Disord, 2002Chouker et al, Nucl Med Commun, 2001 FDOPA7%-13% reduction/yearMoorish et al, Brain, 1996Nurmi et al, Ann Neurol, 2001
CALM-PD CIT: GoalsTo assess the effect of initial pramipexole or carbidopa levodopa treatment on percentage change from baseline in striatal [123I]-CIT uptake, a marker of dopamine transporter density, in a cohort of early PD patients during a 4-year period
CALM-PD CIT: RationaleDopamine transporter imaging with [123I]-CIT/SPECT is a biomarker for PD onset, severity, and progressionIn vitro and animal studies suggest that pramipexole may protect and that levodopa may either protect or damage dopamine neurons
Study DesignScreen Baseline Scan Month 22 Scan Week 10 Scan CALM- CITCALM- PD821378Study DrugMonth 34 Scan Month 46 Scan 7165
Percentage Change in Striatal -CIT Uptake from Baseline by Treatment30201001001020304050Scan Interval (mo)LevodopaPramipexole(39)(36)(35)(33)(32)(39)% Change from Baseline
Correlation of Percentage Change in Striatal CIT Uptake and Changein Off UPDRS22 mo34 mo46 mo (n = 78)(n = 71)(n = 65)Striatumr = 0.01 r = 0.30r = 0.40 P = .94 P = .01P = .001
ConclusionsPatients initially treated with pramipexole demonstrated a reduction in the percentage loss from baseline of striatal [123I]-CIT uptake, a marker of dopamine neuron degeneration, of approximately 40% compared with those initially treated with levodopa during a 46-month evaluation period
CALM - PD Pramipexole versus Levodopa in Early Parkinsons Disease: A 4-Year Randomized Controlled TrialConceived and Conducted by the Parkinson Study Group
University of Rochester Rochester, New York
ObjectivesTo compare initial treatment with pramipexole vs levodopa in early Parkinsons disease (PD) with respect to: The development of:Dopaminergic complicationsOther adverse events, and Changes in:Unified Parkinsons Disease Rating Scale (UPDRS)Quality of life (QOL)
Study DesignEscalation PhaseFollow-up Period 1Follow-up Period 2Total Follow-up Time: 4 yrs to 4 yrs-10 moOct. 96Aug. 01Feb. 00
Outcome VariablesTime to first motor complication:Dyskinesias, wearing-off, or on-offSeverity of dyskinesiasAdverse eventsUPDRSPart I (mental), Part II (ADL), Part III (motor)Quality of lifeEuroQol PDQUALIF
52%74%Dyskinesia, Wearing Off, or On-Off Effects
54%24%
Reasons for Termination Somnolence 111Edema 60Dyskinesias 03 Worsened PD Symptoms 88Nausea/Vomiting 46Mental Issues (hallucinations, confusion, other) 4 4
Lost Interest 108Lost to Follow-up 11Other Symptoms & Comorbidities16 12Did Not Consent to Extension 8768 50 Pramipexole Levodopa
ConclusionsInitial pramipexole reduced the 4-year risk of developing the first dopaminergic event (p < .0001), dyskinesias (p < .0001) and wearing off (p = .02).
ConclusionsInitial levodopa associated with greater improvement in total (p = .008), motor (p = .01), and ADL (p = .03) subscales of the UPDRS.
ConclusionsInitial pramipexole associated with more somnolence, edema, and cellulitis.
Comparable effects of initial pramipexole or levodopa on quality of life scores.
Should I start my PD patients on levodopa or pramipexole?Pramipexole or Levodopa treatment optionsLevodopa Superior symptomatic UPDRS benefitLess somnolence and edemaPramipexole Reduced dopaminergic motor complications Slower decline in dopamine transporter loss as measured by -CIT SPECT uptake
This image represents the pre and postsynaptic dopamine receptors. B-CIT binds to the presynaptic receptor at the dopamine transporter site (shown here in green).
The distribution and intensity of radioactivity as measured by SPECT is a marker for the number of functioning nerve cells in the substantia nigra.