Simuni_Cardiology_book_temp 28/09/2009 13:22 Page 28
Neurodegenerative Diseases Parkinson’s Disease
of agents compared with other dopaminergic therapies. These include study.
23
This prospective, double-blind trial randomized 186 patients with
higher risk for somnolence, confusion, orthostatic hypotension, leg early PD to levodopa versus ropinirole treatment for two years. PET
edema, and the more recently reported entity of impulse control images were obtained at four weeks (baseline) and then at two years.
disorders (ICDs). For example, a recent cross-sectional study of 3,090 The primary outcome measured was the mean percentage reduction in
treated PD patients reported an overall prevalence of ICD of 13.6% and a side-to-side averaged putamen
18
F-dopa uptake. At two years the study
prevalence of ICD of 17.1% in patients treated with a dopamine agonist.
21,22
found a lower percentage of reduction in the ropinirole group (-14.1%)
The advantage of dopamine agonists in delaying onset of motor compared with the levodopa group (-22.9%; p<0.001).
complications has to be weighed against the lower efficacy of dopamine
agonists compared with levodopa and the higher risk of adverse events. These studies, which used different dopamine agonists (pramipexole
and ropinirole), different ligands, and different imaging techniques (PET
The Concept of Neuroprotection in and SPECT), demonstrate consistent results, pointing to a potential
Parkinson’s Disease neuroprotective effect of dopamine agonists. However, interpretation
There have been major advances in symptomatic treatment of PD of of these results is limited by the concern of potential pharmacokinetic
late. This is particularly true for the motor manifestations of the disease. up- or downregulation of the transporter binding and lack of a placebo
Despite this progress, there remain no agents proven to slow or arrest arm. To date, there is no proven neuroprotective effect of dopamine
the progression of the disease. Moreover, defining neuroprotection and agonists in PD.
identifying proper metrics by which to measure neuroprotective benefit
has been challenging. The potential neuroprotective effect of rasagiline was examined in two
studies. The TEMPO study discussed above had a delayed-start
The ELLDOPA study discussed earlier investigated the effects of extension study in which subjects who were initially randomized to
levodopa as a possible neuroprotective agent.
8
After the washout period, placebo were switched to active therapy after the first 26 weeks of
the continued benefit seen in the levodopa-treated cohort over placebo treatment.
9
The degree of disability was measured by the UPDRS score
was felt to possibly be evidence of a neuroprotective benefit. However, at 12 months.
9
Subjects treated with rasagiline from the beginning had
confounding this is the notion that levodopa may have a prolonged a statistically significant reduction of progression of disability
therapeutic effect lasting beyond the two-week washout period used in compared with those started six months later. The larger ADAGIO study
that study. The study also utilized single photon emission computed was launched to confirm the disease-modifying benefit of rasagiline.
24
tomography (SPECT) imaging labeled with 2beta-carboxymethoxy-3beta This trial also used a delayed-start design similar to the TEMPO study
(4-iodophenyl) tropane (β-CIT) (DAT) as the surrogate marker of disease but was larger (n=1,176) and had a longer duration (72 weeks). Patients
progression. Imaging data demonstrated an accelerated loss of were started on either placebo or rasagiline (1 or 2mg) in the first phase
dopaminergic transporter uptake in the levodopa groups relative to the of the trial (36 weeks). In the second phase, all patients were treated
placebo group at 40 weeks. It is unclear whether this result reflects a true with active drug, still blinded to the dosage assignment. This design
negative impact of levodopa on the rate of progression of the allows exploration of the potential neuroprotective benefit of a drug
neurodegenerative process or represents a pharmacokinetic/ that also has a symptomatic effect. If the drug has a purely
pharmacodynamic effect of levodopa causing downregulation of symptomatic benefit, the impact on disability should be the same at the
dopamine transporter uptake. Additional studies will be necessary to end of the study independent of the time of initiation of treatment.
clarify the discrepancy between the clinical and imaging outcomes of the However, if the drug has a neuroprotective benefit, the difference
study. Currently, there are no definitive data on the neuroprotective between the early treatment group versus the delayed treatment group
effect of levodopa and no data demonstrating a neurotoxic effect of at the end of the study will reflect such effect. The study was
levodopa. Such information is important to communicate to the patients completed and presented at the meeting in poster format, but full data
as the concern of levodopa toxicity frequently becomes the reason for are not yet available. The presented data supported a positive impact of
inappropriate delay of initiation of levodopa therapy. early initiation of rasagiline 1mg on delaying progression of motor
disability in early PD. Interestingly, the 2mg dose did not reach all
Dopamine agonists have also been demonstrated to have a primary end-points.
25
neuroprotective effect in tissue culture, but no definitive data exist in
the clinical trials. The previously discussed Parkinson Study Group study The PRECEPT trial looked at the potential neuroprotective properties of
of pramipexole versus levodopa in patients with early PD also used CEP-1347, a mixed-lineage kinase inhibitor.
10
The rationale for the study is
β-CIT imaging (DAT) as a surrogate marker of disease progression in a the ability of CEP-1347 to blockade apoptotic pathways implicated in the
subset of patients over four years.
9
β-CIT imaging was performed at pathogenesis of PD. In the trial, 806 subjects were randomized equally
22, 34, and 46 months. The study found that at each of these evaluation into four groups to receive CEP-1347 at doses of 10mg twice a day, 25mg
periods there was decreased loss of DAT binding in the pramipexole twice a day, 50mg twice a day, or matching placebo. The primary clinical
group compared with levodopa (p=0.004, 0.009, and 0.001 at 22, 34, and end-point was time to development of disability requiring dopaminergic
36 months, respectively). therapy. Secondary end-points examined changes in the UPDRS and
β-CIT SPECT DAT imaging. After an average of 21.4 months of follow-up,
A similar study was conducted to compare the impact of ropinirole the pre-specified interim data analysis concluded that it would be futile
versus levodopa on the rate of loss of dopaminergic neurons using to continue treatment with CEP-147, and the study was terminated. At
18
F-dopa positron emission tomography (PET) imaging in the REAL-PET the time of study termination, 57% of patients receiving placebo reached
28 US NEUROLOGY
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