Dear Hans:

It is interesting how the lay press and media have taken the article and
spun out that mirapex delays the progression of Parkinson's Disease.

THAT IS NOT WHAT THE ARTICLE SAYS.  It is important to read the article
carefully.

1)  What these people measured was radioactive CIT uptake.  They also
measure the progression of clinical disease by doing UPDRS scales scores.

2)  Although the CIT uptake is ASSUMED to be a measure of disease
progression, the investigators themselves stated "in prior longitudinal
studies there has been NO CLEAR CORRELATION between change in [123I]betaCIT
or [18F]DOPA uptake and the change in the UPDRS score.

3)  Indeed this study also confirmed that LACK of correlation between the
radioisotope uptake and the clinical measures of disease progression.

4)  They showed slowing down of the decay in radioactive CIT uptake in
patients treated with pramipexole,, but they were UNABLE to show that at 34
or 46 months there was any difference in the clinical UPDRS scores in favor
of pramipexole.

5)  They were very cagey in how they have fed the data to the press.  They
indicate that they "correlated" their results with the UPDRS scale.  What
they did not indicate is that when they "correlated" the CIT data with the
UPDRS scale, they found NO CORRELATION.

6)  Thus, the claim of slowing down the disease progression is specious.

7)  Does it surprise you that the research, the article and the publicity
have been funded by Pharmacia and Boehringer Ingelheim who manufacture and
distribute pramipexole?

8)  There were many excellent contributors to the data - from major US and
international centers.  Even in the summary of the data they were honest in
their conclusion:  These imaging data highlight the need to further compare
imaging and clinical endpoints of PD progression in long term studies."

9)  THe article states the facts;  the media and press releases that have
followed the article have distorted the findings beyond recognition.

They DO NOT CLAIM THAT THE FOUND THAT PRAMIPEXOLE SLOWS DOWN THE PROGRESSION
OF THE DISEASE.

Jorge A Romero, MD
3600 Gaston Ave
Wadley Tower Suite 455
Dallas, Texas 75246

----- Original Message -----
From: "Hans van der Genugten" <[log in to unmask]>
To: <[log in to unmask]>
Sent: Thursday, April 04, 2002 9:58 AM
Subject: Fw: Mirapex Slows Progression of PD


> Source:    JAMA. 2002;287:1653-1661
> Date:        04/03/2002
>
> The following article appeared in the Journal of the American Medical
> Association 3 April 2002. The report was modified by Dr Abe Lieberman
> for educational purposes to make it more readable for lay people with PD.
>
> SPECT Imaging to Assess the Effects of Mirapex compared to Levodopa
> on Parkinson Disease Progression
>
> Parkinson Study Group
>
> Abstract
> Dopamine Transporter Imaging to Assess the Effects of Pramipexole
> versus Levodopa on the Progression of Parkins Disease (original title)
>
> Context  Pramipexole (mirapex) and levodopa are effective medications to
> treat motor symptoms of early Parkinson disease (PD). In vitro and animal
> studies suggest that pramipexole may protect and that levodopa may either
> protect or damage dopamine neurons. Neuroimaging offers the potential of
> an objective biomarker of dopamine neuron degeneration in PD patients.
>
> Objective  To compare rates of dopamine neuron degeneration after initial
> treatment with pramipexole or levodopa in early PD by means of dopamine
> transporter imaging using single-photon emission computed tomography
> (SPECT) with 2-carboxymethoxy-3(4-iodophenyl)tropane (-CIT) labeled with
> iodine 123.
>
> Design  Substudy of a parallel-group, double-blind randomized clinical
> trial.
>
> Setting and Patients  82 patients with early PD who were recruited at 17
> clinical sites in the United States and Canada and required dopaminergic
> therapy to treat emerging disability, enrolled between November 1996 and
> August 1997.
>
> Interventions  Patients were randomly assigned to receive pramipexole, 0.5
> mg 3 times per day with levodopa placebo (n = 42), or carbidopa/levodopa,
> 25/100 mg 3 times per day with pramipexole placebo (n = 40). For patients
> with residual disability, the dosage was escalated during the first 10
> weeks, and subsequently, open-label levodopa could be added. After 24
> months of follow-up, the dosage of study drug could be further modified.
>
> Main Outcome Measures  The primary outcome variable was the percentage
> change from baseline in striatal [123I]-CIT uptake after 46 months. The
> percentage changes and absolute changes in striatal, putamen, and caudate
> [123I]-CIT uptake after 22 and 34 months were also assessed. Clinical
> severity of PD was assessed using the Unified Parkinson Disease Rating
> Scale (UPDRS) 12 hours off anti-PD medications.
>
> Results  Sequential SPECT imaging showed a decline in mean (SD) [123I]-CIT
> striatal uptake from baseline of
>
> 10.3% (9.8%) at 22 months
>
> 15.3% (12.8%) at 34 months
>
> and 20.7% (14.4%) at 46 monthsapproximately 5.2% per year.
>
>  (Comment: it's estimated the 'normal' age related loss of of striatal
> uptake is 0.6% per year.  This is a measure of the loss of dopamine nerve
> cells in the substantia nigra.  In PD  the 5.2% loss per year in this
> study is 8.6 times higher than the 'normal' age related loss.  In other
> words, PD represents about an 8 fold increase in the loss of dopamine
> neurons per year).
>
> The mean percentage loss in striatal [123I]-CIT uptake from baseline
> was significantly reduced in the pramipexole group compared with the
> levodopa group:
>
> 7.1% for pramipexole versus vs 13.5% for levodopa at 22 months.  This
> change was NOT significant
>
> 10.9%  for pramipexole versus vs 19.6%  for levodopa at 34 months.  This
> change was significant.
>
> 16.0%  for pramipexole versus 25.5%  for levodopa at 46 months.  This
> change was significant.
>
> The percentage loss from baseline in striatal [123I]-CIT uptake was
> correlated with the change from baseline in UPDRS at the 46-month
> evaluation.
>
> Conclusions  Patients initially treated with pramipexole demonstrated a
> reduction in loss of striatal [123I]-CIT uptake, a marker of dopamine
> neuron degeneration, compared with those initially treated with levodopa,
> during a 46-month period. These imaging data highlight the need to further
> compare imaging and clinical end points of PD progression in long-term
> studies.
>
> JAMA. 2002;287:1653-1661
>
> Introduction: Parkinson disease (PD) is a slow but relentlessly
> progressive neurodegenerative disorder characterized clinically by
> bradykinesia, tremor, rigidity, and gait dysfunction. The clinical decline
> reflects ongoing nigral dopamine degeneration.Dopamine replacement
> therapy with levodopa or agonists that stimulate the dopamine receptor is
> effective in ameliorating many signs and symptoms of early PD. However,
> progressive neuronal degeneration ultimately results in severe motor,
> mental, and functional disability.
>
> Increasing evidence from laboratory and animal studies suggests that in
> addition to their symptomatic effects, levodopa and dopamine receptor
> agonists may either accelerate or slow the dopaminergic degeneration of
> PD. Recent data regarding the effects of levodopa have been controversial
> with in vitro data supporting both a potential toxic and protective effect
> on dopaminergic neurons Studies have demonstrated that dopamine receptor
> agonists protect cultured dopaminergic neurons from potential levodopa
> toxicity and may exert direct antioxidant and receptor-mediated
> ant-iapoptotic effects (slow down cell suicide).
>
> During the past decade, in vivo imaging of the nigrostriatal dopaminergic
> system has been developed as a research tool to monitor progressive
> dopaminergic neuron loss in PD. Several reports have demonstrated that at
> the time of emergence of PD symptoms there is a loss of approximately 40%
> to 60% of dopamine markers in the striatum. In longitudinal studies of PD
> progression, imaging ligands targeting both dopamine metabolism fluorine
> 18 fluorodopa ([18F]DOPA) and dopamine transporter density iodine 123
> (2-carboxymethoxy-3[4-iodophenyl]tropane [123I]-CIT) and fluorine 18
> (2-carboxymethoxy-3tropane [18F]CFT) using both positron emission
> tomography and single-photon emission computed tomography (SPECT) have
> demonstrated an annualized rate of reduction in striatal [18F]DOPA,
> [18F]CFT, or [123I]-CIT uptake of approximately 6% to 13% in patients with
> PD compared with 0% to 2.5% change in healthy controls.
>
>      The above imaging studies are consistent with pathological studies
> showing that the rate of nigral degeneration in patients with PD was 8- to
> 10-fold that of healthy, age-matched controls.
>
>      We have used in vivo imaging of the dopamine transporter with
> [123I]-CIT and SPECT to assess the progression of dopaminergic
> degeneration in a subset of patients with early PD participating in a
> clinical trial that compared the option of initial treatment with
> pramipexole with the option of initial treatment with levodopa. The
> clinical study (called CALM-PD) was a multicenter, parallel-group,
> double-blind, randomized clinical trial comparing the option of initial
> treatment with pramipexole or levodopa with regard to the development of
> dopamine motor complications and changes associated with function and
> quality of life.
>
> After 2 years of prospective follow-up, initial treatment with pramipexole
> delayed the onset of dopaminergic motor complications compared with
> levodopa therapy but initial levodopa therapy was more effective than
> pramipexole in ameliorating signs and symptoms of PD. In this report, we
> present the 4-year follow-up of the subset of study patients who have
> undergone sequential [123I]-CIT SPECT imaging to compare the rate of loss
> of the dopamine transporter, a marker for dopamine nerve terminal loss,
> between the groups treated initially with pramipexole or levodopa.
>
>
>  METHODS: The methods and outcomes of the imaging substudy, called
> CALM-PD-CIT, are described herein. The CALM-PD clinical outcomes at 4
> years are reported separately. A total of 82 of the 301 patients in the
> CALM-PD trial, enrolled between November 1996 and August 1997,
> participated in the imaging substudy. Research participants in the imaging
> substudy were recruited at 17 clinical sites (14 in the United States and
> 3 in Canada) and traveled to the imaging center in New Haven, Conn, for up
> to 4 imaging assessments.
>
> CALM-PD:  Eligible patients were randomized with equal allocation to each
> of the 2 treatment groups (pramipexole group or carbidopa/levodopa group)
> using a computer-generated randomization plan.  All patients enrolled at
> sites that chose to participate in the imaging substudy were offered the
> option, but were not required to participate in the -CIT SPECT substudy.
> Baseline imaging was completed prior to randomization.
>
> Patients took study drugs orally 3 times daily, approximately 6 (SD, 2)
> hours apart, throughout the study. Initially patients entered a 10-week
> dosage escalation period to reach one of the predetermined dosage levels:
> 1.5 mg of pramipexole or 75 or 300 mg of carbidopa/levodopa (level 1
> dosage); 3.0 mg of pramipexole or 112.5 or 450 mg of carbidopa/levodopa
> (level 2 dosage); or 4.5 mg of pramipexole or 150 or 600 mg of
> carbidopa/levodopa (level 3 dosage). Study drug was then maintained at
> that level until 24 months after baseline, and subsequently the dosage
> level could be modified during an additional 22- to 36-month evaluation
> period. Patients with emerging disability posing a threat to ambulation,
> activities of independent living, or gainful employment were prescribed
> open-label carbidopa/levodopa as needed.
>
> CALM-PD-CIT[123I]-CIT and SPECT Substudy
> All patients in CALM-PD-CIT were evaluated sequentially with imaging
> studies at baseline and 22, 34, and 46 months after baseline  Four
> contiguous brain slices with the highest uptakes in striatum were
> identified for anaylysis.
>
>      All study participants were evaluated after 12 hours without study
> drug and anti-PD medications, the "defined off" state, with Unified
> Parkinson Disease Rating Scale (UPDRS) and Hoehn and Yahr scores
> determined at the imaging center before each imaging study. The clinical
> investigator was blinded to treatment assignment.
>
>     The primary outcome variable in this study was the percentage change
> from baseline to month 46 in the specific striatal [123I]-CIT uptake
> ratio, a tissue equilibrium distribution volume that is linearly related
> to the density of dopamine transporter binding sites in brain.
>
> RESULTS
>
>     During the 46-month evaluation period, 9 patients (21.4%) initially
> treated with pramipexole and 8 patients (20%) initially treated with
> levodopa withdrew  For patients who completed 46 months of follow-up, the
> mean baseline striatal -CIT uptake was 3.0  in the pramipexole group (n =
> 33) vs 2.9 in the levodopa group (n = 32). One patient in the pramipexole
> group withdrew because of worsening PD with hallucinations; 1 patient in
> the pramipexole group and 3 patients in the levodopa group withdrew
> because of worsening medical illness not related to PD.
>
>     The mean percentage loss from baseline of striatal -CIT uptake was
> 10.3% at 22 months, 15.3% at 34 months, and 20.7% t 46 months, declining
> approximately 5.2% per year during the 46-month evaluation period. The
> mean percentage loss from baseline of [123I]-CIT uptake at 46 months was
> greater in the putamen (22.5%) than in the caudate (19.6%). Although there
> was a greater baseline reduction in the side contralateral to initial
> symptoms  the progressive loss of [123I]-CIT uptake in each hemistriatum
> did not differ.
>
>     Analysis of the treatment groups demonstrated that the rate of decline
> in striatal [123I]-CIT uptake from baseline was significantly reduced in
> the group treated initially with pramipexole compared with the group
> treated initially with levodopa (see abstact above)..
>
> Correlation of [123I]-CIT Uptake and UPDRS Score
>
>     The mean total and motor UPDRS scores obtained in the "defined off"
> state were reduced in the levodopa group at 22 months compared with
> baseline and the pramipexole group, but were not significantly different
> from baseline or the pramipexole group by 34 or 46 months. There was a
> correlation of the percentage loss of striatal [123I]-CIT uptake from
> baseline with the change in total UPDRS score from baseline in all
> patients. The percentage loss of putamen and caudate [123I]-CIT uptake
> from baseline showed increasing correlation with the change in UPDRS score
> from baseline as the duration of assessment increased).
>
> COMMENT
>
>      In vivo dopamine transporter imaging with [123I]-CIT SPECT
> demonstrated reduced loss of striatal [123I]-CIT uptake in patients with
> PD treated initially with pramipexole compared with those treated
> initially with levodopa during a 46-month evaluation period. As [123I]-CIT
> SPECT is a quantitative biomarker for striatal dopamine neuron terminals,
> these data indicate that treatment with pramipexole, levodopa, or both may
> modify the dopaminergic neuronal degeneration of PD.
>
>     The identification of disease-modifying therapies for PD is a major
> unmet need. Studies that evaluate neuroprotective effects of medications
> have been limited by the lack of a clear end point defining
> neuroprotection and confounded by potential simultaneous symptomatic and
> neuroprotective benefit In vivo imaging offers the potential of an
> objective method to monitor neuronal degeneration unaffected by a
> short-term symptomatic drug effect.
>
>     Several recent studies have used neuroimaging to investigate the
> possible neuroprotective effects of dopamine agonists. A preliminary study
> that assessed the effects of ropinirole hydrochloride did not demonstrate
> a change in neuronal loss as measured by [18F]DOPA positron emission
> tomography, but showed a trend toward reduction in the change of [18F]DOPA
> uptake in the patients treated with the dopamine agonist. . We now present
> data demonstrating a significant and persistent reduction in the rate of
> loss of [123I]-CIT uptake in patients with PD initially treated with
> pramipexole compared with levodopa during the 46-month evaluation period.
>
>     Evidence from animal studies, healthy humans, and patients with PD has
> demonstrated that [123I]-CIT uptake is a biomarker for striatal dopamine
> transporter density and also dopamine neuronal terminal integrity.
> Progressive nigrostriatal dopamine neuron loss is the predominant
> pathologic finding of PD. Therefore, the relative reduction in the rate of
> loss of [123I]-CIT uptake in those patients treated with pramipexole
> compared with levodopa most likely reflects a reduction (by pramipexole)
> in the progressive loss of striatal dopamine neuronal function.
>
>     Approximately 20% of the study cohort withdrew from CALM-PD-CIT before
> the month 46 visit. However, in both treatment groups, the baseline
> transporter density measurements in patients who withdrew from the trial
> were similar to those in patients who completed the trial. The frequency
> and reasons for withdrawal were also similar in the 2 groups and the
> treatment effects were reasonably consistent over time. For all of these
> reasons, we do not believe that participant withdrawal had a major impact
> on the overall results.
>
>     Since this study compared 2 active medications without a placebo
> group, these data cannot directly distinguish whether the difference in
> the rate of loss of [123I]-CIT uptake in the treatment groups results from
> a decrease due to pramipexole, an increase due to levodopa, or both.
> However, indirect evidence from preclinical studies and prior imaging
> studies suggests that a decrease in the percentage loss of [123I]-CIT
> uptake due to exposure to pramipexole rather than an increase due to
> exposure to levodopa is more likely.
>
>     In prior imaging studies, the annual percentage loss of [123I]-CIT
> striatal uptake of untreated patients with PD was 6.8%, similar to the
> levodopa group in this study. These imaging data suggest that treatment
> with pramipexole may have decreased the rate of loss of [123I]-CIT uptake
> despite treatment with levodopa. However, the duration and dose of
> exposure to supplemental levodopa and the effect of pretreatment with a
> dopamine agonist on a possible levodopa disease-modifying effect have not
> been fully evaluated. Studies are under way to directly assess the effect
> of treatment with levodopa compared with placebo on the rate of loss of
> [123I]-CIT uptake in patients with early PD that will further elucidate
> the relative effects of pramipexole and levodopa on [123I]-CIT uptake.5
>
>     A key issue is whether the effects of pramipexole and levodopa on the
> rate of loss of [123I]-CIT uptake are associated with a persistent change
> in clinical function in patients with PD. Several clinical end points for
> progressive functional decline in PD have been used, including UPDRS in
> the "defined off" state or after drug washout up to 2 weeks, time to need
> for dopaminergic therapy, or time to the development of motor
> fluctuations. These end points reflect the complex clinical progression of
> PD symptoms and disability. The changes in imaging outcome measures such
> as [123I]-CIT provide a method to assess the striatal dopamine pathologic
> features of PD. In several cross-sectional studies of PD cohorts, the
> reduction in [123I]-CIT correlates with the increasing severity measured
> by the UPDRS.However, in prior longitudinal studies, there has been no
> clear correlation between change in either [123I]-CIT or [18F]DOPA uptake
> and the change in UPDRS score.
>
>     Several explanations for this poor correlation have been suggested.
> First, the UPDRS score is likely confounded by the effects of anti-PD
> medications, despite patient evaluation in the "defined off" state because
> of long-duration effects of these treatments. Second, in early PD the
> temporal patterns for rate of loss of dopamine transporter and the change
> in UPDRS score may not be congruent. This is best illustrated by data
> demonstrating a loss of approximately 40% to 50% of striatal [123I]-CIT
> uptake at the time of diagnosis when clinical symptoms measured by the
> UPDRS may be minimal. These data suggest that in patients with early PD
> clinical and imaging outcomes provide complementary data and that
> long-term follow-up will be required to correlate changes in clinical and
> imaging outcomes. In this study, the loss of striatal [123I]-CIT uptake
> from baseline was significantly correlated with the change in UPDRS score
> from baseline at the 46-month evaluation, suggesting that the correlation
> between clinical and imaging outcomes will emerge with longer monitoring.
>
>     This study demonstrates that [123I]-CIT SPECT imaging can detect
> treatment-related changes in the progressive rate of loss of striatal
> dopamine transporters in patients with early PD. During a 46-month
> evaluation period, these data show a decrease in the rate of loss of
> striatal [123I]-CIT uptake in patients initially treated with pramipexole
> compared with levodopa.
>
> ----------------------------------------------------------------------
> To sign-off Parkinsn send a message to:
mailto:[log in to unmask]
> In the body of the message put: signoff parkinsn

----------------------------------------------------------------------
To sign-off Parkinsn send a message to: mailto:[log in to unmask]
In the body of the message put: signoff parkinsn